Chapter 32: Prostate Cancer

Avni Shah; Wenhui Zhu; William L. Dahut

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence:

233,000 (Estimated new cases for 2014 in the United States) 152 per 100,000 males per year

Stage at Presentation

Deaths:

Estimated 29,480 in 2014

Stage I:

50%

Median age:

66 years

Stage II:

20%

Stage III:

17%

Stage IV:

13%

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Surveillance, Epidemiology and End Results (SEER) Program, available from http://seer.cancer.gov (accessed in 2013)

Pathology

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Pathology

Adenocarcinoma (acinar):

>95%

Gleason Score at Presentation

Ductal adenocarcinoma^✫:

<1%

(Radical prostatectomy specimens)

Mucinous^✫:

<1%

2–4:

Small cell^✫:

<1%

5–6:

54%

Transitional cell^✫:

<1%

30%

Small cell^✫:

<1%

8–9:

10%

^✫Poor prognosis

Kantoff PW et al. Prostate Cancer: Principles & Practice. Philadelphia: Lippincott

Work-up

Bone scan if:

T1 and PSA >20

T2 and PSA >10

Gleason > or >8

T3/T4 disease

Symptomatic

Pelvic CT/MRI if:

T3/T4

T1/2 and normogram indicates probability of LN invasion >10%

Staging

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Staging

Primary Tumor (T)

Primary tumor cannot be assessed

No evidence of primary tumor

Clinically inapparent tumor neither palpable nor visible by imaging

T1a

Tumor incidental histologic finding in 5% or less of tissue resected

T1b

Tumor incidental histologic finding in more than 5% of tissue resected

T1c

Tumor identified by needle biopsy (eg, because of elevated PSA)

Tumor confined within prostate^✫

pT2

Organ confined

T2a

Tumor involves one-half of 1 lobe or less

pT2a

Unilateral, one-half of 1 side or less

T2b

Tumor involves more than one-half of 1 lobe but not both lobes

pT2b

Unilateral, involving more than one-half of side but not both sides

T2c

Tumor involves both lobes

pT2c

Bilateral disease

Tumor extends through the prostate capsule^†

pT3

Extraprostatic extension

T3a

Extracapsular extension (unilateral or bilateral)

pT3a

Extraprostatic extension or microscopic invasion of bladder neck^‡

T3b

Tumor invades seminal vesicle(s)

pT3b

Seminal vesicle invasion

Tumor is fixed or invades adjacent structures other than seminal vesicles: such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall

pT4

Invasion of rectum, levator muscles, and/or pelvic wall

Note: There is no pathologic T1 classification

^✫Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c

^†Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2

^‡Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease)

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Staging

Staging Groups

Group

PSA

Gleason

T1a–c

PSA <10

Gleason ≤6

T2a

PSA <10

Gleason ≤6

T1–2a

PSA X

Gleason X

IIA

T1a–c

PSA <20

Gleason 7

T1a–c

PSA ≥10 <20

Gleason ≤6

T2a

PSA <20

Gleason ≤7

T2b

PSA <20

Gleason ≤7

T2b

PSA X

Gleason X

IIB

T2c

Any PSA

Any Gleason

T1–2

PSA ≥20

Any Gleason

T1–2

Any PSA

Gleason ≥8

III

T3a–b

Any PSA

Any Gleason

Any PSA

Any Gleason

Any T

Any PSA

Any Gleason

Any T

Any N

Any PSA

Any Gleason

When either PSA or Gleason is not available, grouping should be determined by T stage and/or either PSA or Gleason as available

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010

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Staging

Regional Lymph Nodes (N)

Regional lymph nodes were not assessed

pNX

Regional nodes not sampled

No regional lymph node metastasis

pN0

No positive regional nodes

Metastasis in regional lymph node(s)

pN1

Metastases in regional node(s)

15-Year Relative Survival

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15-Year Relative Survival

Stages I-II

81%

Stage III

57%

Stage IV

Predicting 15-year Prostate Cancer Specific Mortality After Radical Prostatectomy

Gleason Score

Mortality (from PrCa)

0.2%–1.2%

3+4/4+3

4.2%–6.5%/6.6%–11%

8–10

26%–37%

Eggener et al. J Urol 2011;185:869–875

Distant Metastasis (M)

No distant metastasis

Distant metastasis

M1a

Nonregional lymph node(s)

M1b

Bone(s)

M1c

Other site(s) with or without bone disease

Note: When more than 1 site of metastasis is present, the most advanced category is used. pM1c is most advanced

10-Year Free Disease Survival

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10-Year Free Disease Survival

(After radical prostatectomy for localized disease)

Gleason score 2-4

96%

Gleason score 5-6

82%

Gleason score 7

52%

Gleason score 8-9

35%

Expert Opinion

Screening for prostate cancer:

The optimal use of PSA in the diagnosis of prostate cancer remains a subject of continued controversy. In 2012 the USPSTF recommended against the use of PSA-based screening for prostate cancer to the general population, regardless of age. The American Urological Association has also revised their guidelines in response, advising against routine PSA based screening. However, in high-risk men ages 40–54 or all men between 55–69 the AUA advises the test to be a man's decision after a discussion of the full understanding of the risks and benefits of testing. Both groups agree that men above the age of 70 or under the age of 40 do not undergo screening

http://annals.org/article.aspx?articleID=1216568 (The Annals of Internal Medicine article for the USPSTF by Virginia A Moyer, 17 July 2012)

http://www.auanet.org/education/guidelines/prostate-cancer-detection.cfm (AUA guidelines)

The traditionally employed PSA threshold of 4 ng/mL has only a 70–80% sensitivity and 60–70% specificity. The positive predictive value of a PSA between 4 and 10 ng/mL is only 25%, and approximately 20% of patients with PSA between 2 and 4 ng/mL will have prostate cancer on biopsy. Free PSA percentage (<10%) has been shown to improve the positive predictive value in patients with total PSA between 4 and 10 ng/mL. In the Prostate Cancer Prevention Trial, 21.1% of prostate cancers were diagnosed in men with a PSA level between 2.6 and 3.9 ng/mL and 15.4% of the prostate cancers had a Gleason score of 7–10 when PSA was ≤2.5 ng/mL

Initial assessment and staging evaluation:

Patients are stratified at diagnosis for an initial treatment plan based on anticipated life expectancy and clinical symptoms

For asymptomatic patients with life expectancy <10 years, treatment may be delayed until symptoms appear
Once an abnormal digital rectal exam and/or an elevated PSA suggest prostate cancer is present, an ultrasound-guided prostate core biopsy with 10–12 cores is performed to help establish the diagnosis, and the 2 most common cellular patterns of the tumor are graded pathologically using the Gleason scale
Pelvic CT or MRI is recommended for patients with T3/T4 tumor or T1/T2 tumor with a predicted probability of lymph node involvement >20%
Bone scan is recommended for patients with T3/T4 tumor, symptomatic disease, or a T1/T2 tumor with PSA >20 ng/mL or a Gleason score ≥8

Localized prostate cancer:

Patients with newly diagnosed clinically localized prostate cancer are divided into 3 risk groups of occult metastasis and relapse after local initial therapy

Low risk: PSA <10 ng/mL, Gleason score ≤6, T1/T2a tumor
Intermediate risk: PSA 10–20 ng/mL, Gleason score 7, T2b/T2c tumor
High risk: PSA >20 ng/mL, Gleason score 8–10, T3/T4 tumor

Treatment options for localized prostate cancer include active surveillance, radical prostatectomy (RP; including open surgery, laparoscopic, and robot-assisted procedures), and radiation therapy (RT; including high-dose external beam radiation therapy with 3D conformal or intensity-modulated radiation therapy, and brachytherapy with or without external beam therapy)

The treatment decision is based on the probability of organ-confined disease, patient's life expectancy, and risk of relapse and metastasis
Active surveillance is an option for patients with low-risk prostate cancer. Serial biopsy and close PSA monitoring are used to attempt to identify patients who may benefit from definitive local treatment. Some have suggested intervention if PSA doubling time is less than 3 years or Gleason grade progression to a predominant Gleason 4 pattern
For patients with organ-confined disease, both RT and RP remain the standard of care, although surgery is not commonly performed in patients ≤70 years of age
In nonrandomized patient cohort studies RP and RT appear to provide equivalent PSA-free relapse, but differ in the type and frequency of side effects. At 5 years, the rate of event-free survival was 81% for RP, 81% for high-dose external beam radiation therapy, and 83% for brachytherapy in 2991 patients with clinical stage T1-T2 localized prostate cancer treated between 1990 and 1998
Patients undergoing RP should have extended pelvic lymph node dissection (PLND), except those with a low predicted probability of nodal metastasis by nomograms
For T3/T4 disease, RP may be considered for selected patients with well-differentiated tumors. Most high-risk patients will receive XRT plus hormonal ablation
For RP, nerve-sparing procedures with radical retropubic and robotic-assisted laparoscopic prostatectomy are the most common techniques. The main determinants of outcome are PSA level, Gleason score, and the TNM clinical stage. Adverse effects from surgery include incontinence, erectile dysfunction, bladder neck stricture, and bowel incontinence
The biochemical control rate after RT depends largely upon the risk features associated with individual tumors. The probability of biochemical control 5 years after RT without hormonal ablation is 84% for low-risk disease, 62% for intermediate-risk disease, and 43% for high-risk disease

Adjuvant therapies after initial definitive therapies

Adjuvant RT after RP should be considered for patients with positive surgical margins, seminal vesicle involvement, or pathological evidence of T3/T4 disease
Immediate postoperative RT for patients with pathologic T3 disease improves PSA progression-free survival significantly (74% vs. 53% for placebo after 5 years of follow up), although there is no overall survival benefit
Due to exclusion of patients with node positive disease in most clinical trials, it remains unclear whether adjuvant RT after RP should be considered in this subset of patients
Immediate androgen-deprivation therapy (ADT) provides significant overall survival benefit in patients with microscopically positive lymph nodes treated with RP, compared to hormonal therapy started at the time of symptomatic local recurrence or metastasis
Neoadjuvant/adjuvant ADT of 2–3 years in combination with RT is the standard for high-risk patients. Neoadjuvant/adjuvant ADT (for 6 months) in combination with RT may improve progression-free disease and prostate cancer-specific and overall survival for patients with PSA ≤10 ng/mL, a Gleason score ≥7, or radiographic evidence of extraprostatic disease. This needs confirmation in a larger study limited only to intermediate-risk patients

Androgen-deprivation therapy

Optimal ADT includes medical castration with a GnRH antagonist, an LHRH agonist, or surgical castration with bilateral orchiectomy. The addition of an antiandrogen can reduce the initial disease flare that may follow introduction of a LHRH agonist, but does not appear to add significantly to survival
Side effects of ADT include osteoporosis, hot flashes, loss of libido, erectile dysfunction, fatigue, gynecomastia, cognitive dysfunction, depression, anemia, loss of muscle mass, glucose intolerance, and changes in lipids profile and increased risk of cardiovascular disease
Hot flashes from hormonal therapy can be treated with clonidine (0.1 mg daily, orally), low-dose estrogens, or antidepressants
Prophylactic breast XRT can reduce the incidence of painful gynecomastia
Patients receiving long-term ADT should have a baseline bone density scan and supplemental vitamin D and calcium. Consider bisphosphonates if an evaluation demonstrates evidence of either osteopenia or osteoporosis

PSA Failure

PSA failure after RP:

Following RP, it is expected that PSA will be undetectable. Biochemical recurrence following RP is defined as either failure to achieve an undetectable PSA level or a PSA rise after surgery on 2 or more laboratory determinations. The American Urological Association Prostate Guideline Update Panel has chosen a PSA level ≥0.2 ng/mL as the threshold
Patients with biochemical recurrence because of local failure and without distant metastasis (clinical features include PSA <2 ng/mL, slow PSA doubling time, a long interval to failure after surgery) should be evaluated for salvage RT. Salvage RT provides durable disease-free survival in 60–70% of patients, but no confirmed overall survival benefits. Predictors of progression after salvage RT include a Gleason score of 8–10, pre-RT PSA ≤2 ng/mL, negative surgical margins, and a PSA doubling time <10 months

PSA failure after RT:

PSA failure after RT is defined as a PSA rise ≥2 ng/mL above the nadir (the Phoenix definition)
Patients with original clinical stage T1–T2, a life expectancy ≤10 years, and a current PSA <10 ng/mL may be candidates for local therapy such as salvage RP, cryotherapy, or brachytherapy. However, morbidity is high and there are no randomized trials that demonstrate improved survival. Further work-up is indicated to rule out distant metastasis before local therapy

For patients with PSA failure, timing of ADT is affected by PSA velocity, patient preference, and other medical comorbidities. Early implementation of ADT may delay the appearance of metastases; however, there are no data indicating early ADT provides any overall survival benefit

Advanced prostate cancer

In patients with metastatic prostate cancer, local therapies are used primarily for symptom management. There are no conclusive data that local therapies improve survival
ADT should begin immediately in the presence of tumor-related symptoms or overt metastasis
Combined androgen blockage (castration combined with an antiandrogen) provides no definite survival improvement over castration alone in patients with metastatic disease
Initiation of treatment with LHRH agonists is associated with a transient increase in testosterone production with initial use (tumor flare). For patients with overt metastases who are at risk of developing symptoms (such as spinal cord compression, worsening pain, or urinary outlet obstruction) an antiandrogen should be given concurrently with a LHRH agonist for at least 7 days after initiating treatment with the latter to competitively block testosterone at androgen receptors, and prevent potential exacerbation of disease. Ketoconazole may also be used in patients who are at high risk for complications associated with tumor flare
Intermittent ADT can be used to reduce side effects and cost of ADT, but its long-term efficacy remains unproven
Abiraterone acetate has been approved in patients pre-chemotherapy based on improved progression-free survival. The study was stopped before an overall-survival benefit could be seen, but there was a trend towards OS improvement as well [Ryan et al. N Engl J Med 2013;368:138–148]. Enzalutamide may be shown to be beneficial in this setting as well
Second-line hormonal management includes antiandrogens, antiandrogen withdrawal, adrenal androgen inhibitors (aminoglutethimide or ketoconazole with hydrocortisone replacement), and estrogens. Abiraterone acetate targets cytochrome P450 17A1 (CYP17A1), leading to a decrease in the production of testosterone. It received FDA approval based on a study that demonstrated improved survival in patients who received it after docetaxel chemotherapy. Abiraterone acetate is administered daily in combination with prednisone. Enzalutamide, a potent anti-androgen, has also been approved for use post-chemotherapy based on an OS benefit. One advantage of enzalutamide over abiraterone acetate is that it does not require concomitant prednisone which can have side-effects in patients with prostate cancer. Selected patients may respond to sequential hormonal manipulations
Sipuleucel-T is a cellular immunotherapy consisting of peripheral blood mononuclear cells obtained by leukapheresis and cultured (activated) with a recombinant human protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor (PAP-GM-CSF). In a randomized trial this product had no effect on time to progression, but lead to an improvement in overall survival.
Chemotherapy with docetaxel every 3 weeks plus prednisone is the preferred first-line chemotherapy for advanced prostate cancer, providing improved survival. Cabazitaxel is a semisynthetic derivative of a natural taxoid, which, when combined with prednisone, improved survival in patients who had progressed on docetaxel and prednisone. Alternative regimens include every 3-week docetaxel and estramustine, weekly docetaxel and prednisone, and every 3-week mitoxantrone and prednisone
Cabazitaxel is approved as a second-line chemotherapeutic agent
Metastatic small cell carcinoma of the prostate should be treated with a platinum-containing regimen, but mixed tumors (adenocarcinoma and small cell) may have some initial response to hormonal ablation
Zoledronic acid prevents skeletal-related events in patients with castrate resistant prostate cancer and bone metastases
Radium-223 has been approved by the FDA-for prostate cancer and selectively targets bone metastases with alpha particles. It has been shown to improve overall survival but it remains to be seen where exactly it will be used in patients and whether or not it will be combined with other approved agents

American Cancer Society Guidelines for the Early Detection of Cancer. Prostate Cancer Early Detection. Available from: http://www.cancer.org/Cancer/ProstateCancer/MoreInformation/ProstateCancerEarlyDetection/prostate-cancer-early-detection-toc

Gulley JL, Dahut WL. Prostate cancer. In: Abraham J et al. eds. Bethesda Handbook of Clinical Oncology 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:185–201

Parker et al. N Engl J Med. 2013;369:213–223

Pazdur R et al. Cancer Management: A Multidisciplinary Approach. 13th ed. Manhasset, NY: CMP Healthcare Media, Inc; 2010

The Partin Tables. Available from: http://urology.jhu.edu/prostate/partintables.php [last accessed July 8, 2011]

U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;149:185–191, W–42

REGIMEN: ABIRATERONE ACETATE METASTATIC CASTRATION–RESISTANT PROSTATE CANCER—NO PRIOR CHEMOTHERAPY

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Regimen: Abiraterone Acetate Metastatic Castration–Resistant Prostate Cancer—No Prior Chemotherapy

Ryan CJ et al. N Engl J Med 2013;368:138–148

Abiraterone acetate 1000 mg orally once daily, continually for 28 consecutive days (total dose/28-day cycle = 28,000 mg)

Note: No food should be consumed for at least 2 hours before a dose of abiraterone acetate is taken and for at least 1 hour after a dose of abiraterone acetate is taken. Exposure (area under the curve) of abiraterone acetate increases up to 10-fold when abiraterone acetate is taken with meals

Prednisone 5 mg orally twice daily, continually for 28 consecutive days (total dose/28-day cycle = 280 mg)

Notes:

For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the dose of abiraterone acetate to 250 mg once daily
Avoid abiraterone acetate in patients with baseline severe hepatic impairment (Child-Pugh Class C), as abiraterone acetate has not been studied in this population, and no dose adjustment can be predicted
Abiraterone acetate is an inhibitor of the polymorphically expressed cytochrome P450 (CYP) enzyme, CYP2D6
- Avoid coadministration of abiraterone acetate with CYP2D6 substrates that have a low therapeutic index. If an alternative treatment cannot be used, exercise caution and consider a dose reduction of concomitantly used CYP2D6 substrates
Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during, and after stressful situations
Monitor for signs and symptoms of mineralocorticoid excess, including hypokalemia, fluid retention, and hypertension. Prednisone dose may have to be supplemented in some patients or augmented with an aldosterone antagonist such as eplerenone
Use abiraterone acetate with caution in patients with a history of cardiovascular disease. Control hypertension and correct hypokalemia before initiating treatment
Abiraterone acetate is a substrate of CYP3A4. Avoid or use with caution strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifapentine, rifampin) during abiraterone acetate treatment
Abiraterone acetate was a strong inhibitor of CYP1A2 and CYP2D6, and a moderate inhibitor of CYP2C9, CYP2C19, and CYP3A4/5 in experimental systems. It is not yet known whether its effects on CYP1A2, CYP2C subfamily, or CYP3A subfamily enzymes in in vitro systems are representative of a potential for clinically important drug interactions
Use abiraterone acetate with caution in patients with a history of cardiovascular disease. The safety of abiraterone acetate in patients with LVEF <50% or NYHA Class III or IV heart failure is not established. Control hypertension and correct hypokalemia before treatment

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modification

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Treatment Modification

Adverse Event

Dose Modification

G2 hepatotoxicity

Hold abiraterone acetate until toxicity remits to G ≤1, then resume treatment at a dose of 750 mg once daily

G3 hepatotoxicity (elevations in ALT and/or AST >5 × upper limit of normal [ULN] or total bilirubin >3 × ULN) in a patient with baseline normal hepatic function

Withhold abiraterone acetate. Treatment may be restarted at a dose of 750 mg once daily following return of liver function tests to a patient's baseline or to AST and ALT G ≤1 (2.5 × ULN) and total bilirubin G ≤1 (≤1.5 × ULN). For patients who resume treatment, monitor serum transaminases

G3 hepatotoxicity (elevations in ALT and/or AST >5 × upper limit of normal [ULN] or total bilirubin >3 × ULN) in a patient with baseline normal hepatic impairment on a reduced dose of 750 mg/day because of prior hepatotoxicity at 1000 mg/day

Withhold abiraterone acetate. Treatment may be restarted at a dose of 500 mg once daily following return of liver function tests to a patient's baseline or to AST and ALT G ≤1 (2.5 × ULN) and total bilirubin G ≤1 (≤1.5 × ULN). For patients who resume treatment, monitor serum transaminases

G3 hepatotoxicity (elevations in ALT and/or AST >5 × upper limit of normal or total bilirubin >3 × ULN) in a patient with baseline normal hepatic impairment on a reduced dose of 500 mg/day because of prior hepatotoxicity at 750 mg/day

Discontinue abiraterone acetate

G3 hepatotoxicity (elevations in ALT and/or AST >5 × ULN or total bilirubin >3 × ULN) in a patient with baseline moderate hepatic impairment on a reduced dose of 750 mg abiraterone acetate daily

Discontinue abiraterone acetate

G4 hepatotoxicity (elevations in ALT and/or AST >20 × ULN or total bilirubin >10 × ULN) in a patient with baseline moderate hepatic impairment

Discontinue abiraterone acetate

Hypertension, hypokalemia, and fluid retention caused by mineralocorticoid excess

Withhold abiraterone acetate. Ensure corticosteroids are being administered appropriately. Manage hypokalemia and hypertension

Suspicion of adrenocortical insufficiency

Perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Consider administering increased corticosteroid doses during and after stressful situations

Efficacy

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Efficacy

Prespecified Secondary and Exploratory Efficacy End Points^✫

Abiraterone + Prednisone (N = 546)

Prednisone Alone (N = 542)

Value (95% CI)^†

P Value

End Point

Secondary End Points

Median Times in Months to:

Opioid use for cancer-related pain

Not Reached

23.7

0.69 (0.57–0.83)

<0.001

Starting cytotoxic chemotherapy

25.2

16.8

0.58 (0.49–0.69)

<0.001

Decline in ECOG PS by ≥1 point

12.3

10.9

0.82 (0.71–0.94)

0.005

PSA progression^‡

11.1

5.6

0.49 (0.42–0.57)

<0.001

Exploratory End Points^§

Median Times in Months to:

Increase in pain

26.7

18.4

0.82 (0.67–1.00)

0.049

Functional status decline^✫^✫

12.7

8.3

0.78 (0.66–0.92)

0.003

Decline of ≥50% in PSA level (%)^††

2.59 (2.19–3.05)^‡‡

<0.001

Patients with Measurable Disease at Baseline and a RECIST Response (%)

N = 220

N = 218

Defined objective response

2.27 (1.59–3.25)^‡‡

<0.001

Stable disease

Progressive disease

CI, Confidence interval; FACT-P, Functional Assessment of Cancer Therapy–Prostate; HR, hazard ratio; PS, performance score; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors

^✫Percentages may not sum to 100 because of rounding

^†Values are hazard ratios unless otherwise specified

^‡Based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria

^§The exploratory analyses are reported with no adjustment for multiplicity

Increase in pain is defined as an increase in the baseline pain level by 30% or more, as measured by the average of the pain scores on the Brief Pain Inventory–Short Form (range: 0–10, with higher scores indicating worse average pain) at 2 consecutive visits, without a decrease in analgesic use

^✫^✫Defined as months from randomization to the first date a patient has a decrease of 10 points or more on the FACT-P instrument (range: 0–156, with higher scores indicating better overall quality of life)

^††A decline ≥50% in the PSA level was based on modified PCWG2 criteria

^‡‡Values are relative risks

Toxicity

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Toxicity

Adverse Events

Adverse Event

Abiraterone + Prednisone (N = 542)

Prednisone Alone (N = 540)

Number of Patients (%)

Any adverse event

537 (99)

524 (97)

G3/4 adverse event

258 (48)

225 (42)

Any serious adverse event

178 (33)

142 (26)

Adverse event leading to treatment discontinuation

55 (10)

49 (9)

Adverse event leading to death^✫

20 (4)

12 (2)

G1-4 adverse event ≥15% of patients in either group

Fatigue

212 (39)

185 (34)

Back pain

173 (32)

Arthralgia

154 (28)

129 (24)

Nausea

120 (22)

118 (22)

Constipation

125 (23)

103 (19)

Hot flush

121 (22)

98 (18)

Diarrhea

117 (22)

96 (18)

Bone pain

106 (20)

103 (19)

Muscle spasm

75 (14)

110 (20)

Pain in extremity

90 (17)

85 (16)

Cough

94 (17)

73 (14)

Adverse Events of Special Interest^†

Adverse Event

Abiraterone + Prednisone (N = 542)

Prednisone Alone (N = 540)

G 1–4

G 3 or 4

G 1–4

G 3 or 4

Fluid retention or edema

150 (28)

4 (<1)

127 (24)

9 (2)

Hypokalemia

91 (17)

13 (2)

68 (13)

10 (2)

Hypertension

118 (22)

21 (4)

71 (13)

16 (3)

Cardiac disorder^‡

102 (19)

31 (6)

84 (16)

18 (3)

Atrial fibrillation

22 (4)

7 (1)

26 (5)

5 (<1)

ALT increased

63 (12)

29 (5)

27 (5)

4 (<1)

AST increased

58 (11)

16 (3)

26 (5)

5 (<1)

ALT, Alanine aminotransferase; AST, aspartate aminotransferase

^✫Most common adverse events leading to death were general disorders, including disease progression, decline in physical health, and infections including pneumonia and respiratory tract infection

^†Adverse events of special interest were selected on the basis of the safety profile of phase 2 and phase 3 studies of abiraterone

^‡Cardiac disorders included ischemic heart disease, myocardial infarction, supraventricular tachyarrhythmia, ventricular tachyarrhythmia, cardiac failure, and possible arrhythmia-related investigations, signs, and symptoms

Patient Population Studied

Inclusion criteria: (a) metastatic, histologically or cytologically confirmed adenocarcinoma of the prostate; (b) PSA progression according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria or radiographic progression in soft tissue or bone ± PSA progression; (c) ongoing androgen deprivation with a serum testosterone level <50 ng/dL (<1.7 nmol/L); (d) ECOG performance status grade of 0 or 1; (e) no symptoms or mild symptoms, as defined according to the Brief Pain Inventory–Short Form (BPI-SF; scores of 0 to 1 [asymptomatic] or 2 to 3 [mildly symptomatic], respectively). Exclusion criteria: (a) No previous therapy with an antiandrogen; (b) visceral metastases; (c) previous ketoconazole >7 days

Treatment Monitoring

CBC every 8 weeks for the first 24 weeks, and then, every 12 weeks
Evaluation including PSA: Every 8 weeks for the first 24 weeks, and then, every 12 weeks
Monitor blood pressure, serum potassium, and symptoms of fluid retention at least every 8 weeks
Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with abiraterone acetate, every 2 weeks for the first 3 months of treatment, and monthly thereafter. Modify, interrupt, or discontinue abiraterone acetate dosing as recommended
In patients with baseline moderate hepatic impairment receiving a reduced abiraterone acetate dose of 250 mg/day, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every 2 weeks for the following 2 months of treatment, and monthly, thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop
For patients who resume treatment after LFTs return to G ≤1 from a G2/3/4 toxicity, monitor serum transaminases and bilirubin at a minimum of every 2 weeks for 3 months and monthly thereafter
Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during, and after stressful situations

REGIMEN: DOCETAXEL + PREDNISONE

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Regimen: Docetaxel + Prednisone

Tannock IF et al. N Engl J Med 2004;351:1502–1512

Dexamethasone 8 mg/dose orally for 3 doses at 12 hours, 3 hours, and 1 hour before docetaxel treatment commences (total dose/cycle = 24 mg)

Docetaxel 75 mg/m² intravenously over 1 hour, in a volume of 0.9% sodium chloride injection or 5% dextrose injection sufficient to produce a solution with concentration within the range 0.3–0.74 mg/mL, on day 1, every 21 days (total dosage/cycle = 75 mg/m²)

Prednisone 5 mg/dose orally twice daily, continually, for 21 consecutive days, on days 1–21, every 3 weeks (total dose/cycle = 210 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A study of 335 patients with castration-refractory metastatic prostate cancer and no prior chemotherapy other than estramustine

Efficacy

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Efficacy

Docetaxel +

Mitoxantrone +

Prednisone

Median survival

18.9 months (n = 335)

16.5 months (n = 357)

Pain response

35% (n = 153)

22% (n = 157)

50% ↓ PSA

45% (n = 291)

32% (n = 300)

Toxicity (N = 332)

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Toxicity (N = 332)

% All Grades

% G3/4

Hematologic

Neutropenia

—

Anemia

—

Thrombocytopenia

—

Febrile neutropenia

—

Infection

—

Nonhematologic

Fatigue

Nausea/vomiting

—

Diarrhea

Sensory neuropathy

—

Stomatitis

—

Dyspnea

—

Peripheral edema

—

Myalgia

—

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

G4 Neutropenia ≥7 days duration, febrile neutropenia, infection, or ANC <1500/mm³ on day of therapy

Delay therapy until ANC >1500/mm³ or reduce dose of docetaxel by 25%

G3/4 thrombocytopenia

Delay therapy until thrombocytopenia G ≤2, or reduce dosage of docetaxel by 25%

G3/4 toxicities other than those listed above

Wait for toxicity to recover to G ≤1, then reduce docetaxel dosage to 60 mg/m²

G3/4 neurotoxicity

Stop therapy

G4 nonhematologic toxicity that occurs with 60 mg/m² docetaxel

Aspartate/alanine aminotransferase (AST/ALT) >1.5 × upper limits of normal (ULN) and alkaline phosphatase >2.5 × ULN

Bilirubin ≤ ULN

Hold docetaxel until resolved

Therapy Monitoring

Before each cycle: CBC with differential, liver function tests, PSA if indicated

REGIMEN: MITOXANTRONE + PREDNISONE (M + P)

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Regimen: Mitoxantrone + Prednisone (M + P)

Hussain M et al. Semin Oncol 1999;26(5 Suppl 17):55–60

Tannock IF et al. J Clin Oncol 1996;14:1756–1764

Mitoxantrone 12 mg/m² intravenously in 50 mL 0.9% sodium chloride injection or 5% dextrose injection over 5–30 minutes, on day 1, every 21 days (total dosage/cycle = 12 mg/m²)

Prednisone 5 mg/dose orally twice daily continually, for 21 consecutive days, on days 1–21, every 3 weeks (total dose/cycle = 210 mg)

Usually administered for a total of 6 cycles

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Patients with metastatic castration-refractory prostate cancer with symptoms (including pain) and disease progression despite standard hormonal therapy. Randomized comparison with prednisone alone

Efficacy (N = 80)

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Efficacy (N = 80)

Palliative response^✫

29-38%

Palliative response duration

43 weeks

^✫Defined as a decrease in pain parameters

Efficacy: PSA Response (N = 57)

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Efficacy: PSA Response (N = 57)

≥50% decrease

33%

≥75% decrease

23%

Toxicity (N = 654 and 796 cycles)

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Toxicity^✫ (N = 654 and 796 cycles)

% Cycles

% G1/2

% G3/4

Hematologic (N = 796 cycles)

Neutropenia

Febrile neutropenia

Thrombocytopenia

4.2

0.6

Nonhematologic (N = 654 cycles)

Nausea/vomiting

0.5

Alopecia

—

Cardiac dysfunction

2.5

1.7

^✫WHO criteria

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

WBC <3000/mm³, ANC <1500/mm³, or platelet <100,000/mm³

Delay therapy until WBC >3000/mm³, ANC >1500/mm³, platelet >100,000/mm³

Nadir ANC <500/mm³, or nadir platelet <50,000/mm³

Reduce mitoxantrone dosage by 2 mg/m² per dose

Nadir ANC >1000/mm³, and nadir platelet >100,000/mm³, and minimal nonhematologic toxicity

May increase mitoxantrone dosage to 14 mg/m² per dose

Patients who received a total cumulative lifetime mitoxantrone dosage of 140 mg/m²

Stop mitoxantrone, but continue prednisone

Therapy Monitoring

Before starting therapy: Echocardiogram
Before each cycle: CBC with differential, LFTs, PSA if indicated

ADVANCED DISEASE REGIMEN: ABIRATERONE ACETATE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER—PRIOR CHEMOTHERAPY

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Advanced Disease Regimen: Abiraterone Acetate Metastatic Castration-Resistant Prostate Cancer—Prior Chemotherapy

Fizazi K et al. Lancet Oncol 2012;13:983–992

Abiraterone acetate 1000 mg orally once daily on an empty stomach, continually for 28 consecutive days (total dose/28-day cycle = 28,000 mg)

Note: No food should be consumed for at least 2 hours before a dose of abiraterone acetate is taken and for at least 1 hour after a dose of abiraterone acetate is taken. Exposure (area under the curve) of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals

Prednisone 5 mg orally, twice daily, continually for 28 consecutive days (total dose/28-day cycle = 280 mg)

Notes:

For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the dose of abiraterone acetate to 250 mg once daily
Avoid abiraterone acetate in patients with baseline severe hepatic impairment (Child-Pugh Class C), as abiraterone acetate has not been studied in this population, and no dose adjustment can be predicted
Abiraterone acetate is an inhibitor of the polymorphically expressed cytochrome P450 (CYP) enzyme, CYP2D6
- Avoid coadministration of abiraterone acetate with CYP2D6 substrates that have a low therapeutic index. If an alternative treatment cannot be used, exercise caution and consider a dose reduction of concomitantly used CYP2D6 substrates
Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during, and after stressful situations
Monitor for signs and symptoms of mineralocorticoid excess, including hypokalemia, fluid retention, and hypertension. Prednisone dose may have to be supplemented in some patients or augmented with an aldosterone antagonist such as eplerenone
Use abiraterone acetate with caution in patients with a history of cardiovascular disease. Control hypertension and correct hypokalemia before initiating treatment
Abiraterone acetate is a substrate of CYP3A4. Avoid or use with caution strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifapentine, rifampin) during abiraterone acetate treatment
Abiraterone acetate was a strong inhibitor of CYP1A2 and CYP2D6, and a moderate inhibitor of CYP2C9, CYP2C19, and CYP3A4/5 in experimental systems. It is not yet known whether its effects on CYP1A2, CYP2C subfamily, or CYP3A subfamily enzymes in in vitro systems are representative of a potential for clinically important drug interactions
Use abiraterone acetate with caution in patients with a history of cardiovascular disease. The safety of abiraterone acetate in patients with LVEF <50% or NYHA Class III or IV heart failure is not established. Control hypertension and correct hypokalemia before treatment

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modification

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Treatment Modification

Adverse Event

Dose Modification

G2 hepatotoxicity

Hold abiraterone acetate until toxicity remits to G ≤1, then resume treatment at a dose of 750 mg once daily

G3 hepatotoxicity (elevations in ALT and/or AST >5 × upper limit of normal [ULN] or total bilirubin >3 × ULN) in a patient with baseline normal hepatic function

G3 hepatotoxicity (elevations in ALT and/or AST >5 × upper limit of normal [ULN] or total bilirubin >3 × ULN) in a patient with baseline normal hepatic impairment on a reduced dose of 500 mg/day because of prior hepatotoxicity at 750 mg/day

Discontinue abiraterone acetate

G3 hepatotoxicity (elevations in ALT and/or AST >5 × ULN or total bilirubin >3 × ULN) in a patient with baseline moderate hepatic impairment on a reduced dose of 750 mg abiraterone acetate daily

Discontinue abiraterone acetate

G4 hepatotoxicity (elevations in ALT and/or AST >20 × ULN or total bilirubin >10 × ULN) in a patient with baseline moderate hepatic impairment

Discontinue abiraterone acetate

Hypertension, hypokalemia, and fluid retention caused by mineralocorticoid excess

Withhold abiraterone acetate. Ensure corticosteroids are being administered appropriately. Manage hypokalemia and hypertension

Suspicion of adrenocortical insufficiency

Perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Consider administering increased corticosteroid doses during and after stressful situations

Patient Population Studied

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Patient Population Studied

A phase-3, double-blind, randomized placebo-controlled trial, in which men with histologically or cytologically confirmed metastatic castration-resistant prostate cancer were enrolled if they had (a) previous treatment with docetaxel and a maximum of 2 previous chemotherapies; (b) PSA progression according to Prostate Cancer Working Group criteria, or radiographic progression in soft tissue or bone ± PSA progression; (c) ongoing androgen deprivation to maintain serum testosterone concentration lower <50 ng/dL (<2.0 nmol/L by radioimmunoassay); and (d) ECOG performance status ≤2

Abiraterone Acetate + Prednisone

Placebo + Prednisone

Age (years)

Median (range)

69 (42–95)

69 (39–90)

≥75 years

220/797 (28%)

111/397 (28%)

Disease location

Bone

709/797 (89%)

357/397 (90%)

Node

361/797 (45%)

164/397 (41%)

Liver

90/797 (11%)

30/397 (8%)

BPI-SF score for pain^✫

Number of patients

792

394

Median score (range)

3.0 (0–10)

Number of previous cytotoxic chemotherapy regimens

558/797 (70%)

275/398 (69%)

239/797 (30%)

123/398 (31%)

ECOG performance status

0 or 1

715/797 (90%)

353/398 (89%)

82/797 (10%)

45/398 (11%)

Prostate-specific antigen

Number of patients

788

393

Median (range), ng/mL

128.8 (0.4–9253.0)

137.7 (0.6–10114.0)

Gleason score at initial diagnosis

≤7

341/697 (49%)

161/350 (46%)

≥8

356/697 (51%)

189/350 (54%)

PSA at initial diagnosis (ng/mL)

Number of patients

619

311

Median (range)

27.0 (0.1–16065.9)

35.5 (1.1–7378.0)

Previous cancer therapy

Surgery

429/797 (54%)

193/398 (49%)

Radiotherapy

570/797 (72%)

285/398 (72%)

Hormonal

796/797 (100%)

396/398 (100%)

Other^†

797/797 (100%)

398/398 (100%)

Extent of disease^‡

Viscera, not otherwise specified

1 (0%)

0 (0%)

Lungs

103 (13%)

45 (11%)

Prostate mass

60 (8%)

23 (6%)

Other viscera

46 (6%)

21 (5%)

Other tissue

40 (5%)

20 (5%)

BPI-SF, Brief Pain Inventory-Short Form

^✫The BPI-SF rates pain on a scale of 0–10: 0–3 = clinically significant pain is absent; 4–10 = clinically significant pain is present; the scores shown are for the worst pain over the previous 24 hours

^†Including chemotherapy

^‡Data are for the extent of disease in specific/relevant organs; therefore, numbers ≠ 797 and 398

Efficacy

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Efficacy

Progression-Free Survival (PFS) and Objective Response OR

Abiraterone Acetate + Prednisone N = 797 (95% CI)

Placebo + Prednisone N = 398 (95% CI)

Hazard Ratio (95% CI)

p Value

Time to PSA progression (months)^✫

8.5 (8.3–11.1)

6.6 (5.6–8.3)

0.63 (0.52–0.78)

<0.0001

Radiographic PFS (months)^✫

5.6 (5.6–6.5)

3.6 (2.9–5.5)

0.66 (0.58–0.76)

<0.0001

PSA response (%)^†

235 (29.5%)

22 (5.5%)

—

<0.0001

OR by RECIST (%)^‡

118 (14.8%)

13 (3.3%)

—

<0.0001

RECIST, Response Evaluation Criteria in Solid Tumors

Data are median (95% CI) or number (%)

^✫Calculated from date of randomization to date of PSA progression (per Prostate Specific Antigen Working Group criteria) or date of radiographically documented disease progression or death

^†Proportion of patients with a PSA decline of 50% or higher according to Prostate Specific Antigen Working Group criteria; unstratified analysis

^‡Additional (not secondary) end point

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Efficacy

Overall Survival by Subgroup (Univariate Analysis)

Abiraterone Acetate + Prednisone

Placebo + Prednisone

HR (95% CI)

Events (N)

Median OS (Months; 95% CI)

Events (N)

Median OS (Months; 95% CI)

Baseline ECOG status

0–1

432/715

17.0 (15.6–17.7)

237/353

12.3 (10.8–14.5)

0.74 (0.63–0.87)

69/82

7.3 (6.4–8.6)

37/45

7.0 (4.0–8.1)

0.77 (0.50–1.17)

Pain at study entry

Pain absent (0–3)

244/440

18.4 (17.2–19.9)

137/219

13.9 (11.7–15.9)

0.69 (0.56–0.85)

Pain present (4–10)

257/357

13.3 (11.1–14.7)

137/179

9.3 (7.9–10.7)

0.78 (0.63–0.96)

Previous lines of chemotherapy

329/557

17.1 (15.6–18.2)

185/275

11.7 (10.4–13.9)

0.71 (0.59–0.85)

172/240

14.2 (11.8–15.3)

89/123

10.4 (8.8–13.5)

0.80 (0.61–1.02)

Type of progression before study entry

PSA progression

126/238

18.3 (16.7–20.8)

79/125

13.6 (10.8–16.8)

0.63 (0.47–0.84)

Radiographic progression ± PSA progression

375/559

14.8 (14.0–16.1)

195/273

10.5 (8.9–12.5)

0.78 (0.65–0.93)

Previous docetaxel usage

From first docetaxel dose

494/787

32.6 (30.7–35.0)

274/397

27.6 (25.9–30.3)

0.75 (0.65–0.88)

From last docetaxel dose

494/787

23.2 (22.4–24.5)

274/397

19.4 (17.5–20.8)

0.74 (0.64–0.86)

Reason for discontinuation of docetaxel

Progressive disease

241/362

14.2 (12.0–15.8)

129/182

10.5 (9.3–11.8)

0.77 (0.62–0.97)

All other reasons

258/431

17.0 (15.6–18.2)

145/215

12.6 (10.4–14.9)

0.73 (0.59–0.89)

Treatment of abiraterone acetate plus prednisone started

≤3 Months after last docetaxel dose

144/227

15.0 (13.7–17.4)

82/112

10.7 (8.9–13.0)

0.62 (0.47–0.83)

>3 Months after last docetaxel dose

346/554

16.1 (14.9–17.3)

190/282

11.8 (10.3–14.6)

0.77 (0.64–0.92)

Docetaxel exposure time

≤3 Months

98/140

14.6 (11.9–16.7)

51/69

10.8 (8.4–14.9)

0.76 (0.53–1.08)

>3 Months

252/401

16.2 (14.9–17.3)

223/328

11.2 (10.3–13.6)

0.74 (0.63–0.87)

Patients who were not deceased at the time of analysis were censored on the last date the patient was known to be alive or lost to follow-up

Every test was done at a significance level of 0.05

Patient numbers are not consistent across subgroups because of missing data

Toxicity

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Toxicity

Abiraterone Acetate + Prednisone (n = 791)

Placebo + Prednisone (n = 394)

All Grades N (%)

G3 N (%)

G4 N (%)

All Grades N (%)

G3 N (%)

G4 N (%)

Hematologic

Anemia

198 (25%)

53 (7%)

9 (1%)

110 (28%)

26 (7%)

6 (2%)

Thrombocytopenia

30 (4%)

8 (1%)

3 (<1%)

15 (4%)

1 (<1%)

Neutropenia

8 (1%)

1 (<1%)

2 (<1%)

1 (<1%)

Febrile neutropenia

3 (<1%)

Nonhematologic

Diarrhea

156 (20%)

8 (1%)

1 (<1%)

58 (15%)

5 (1%)

Fatigue

372 (47%)

70 (9%)

2 (<1%)

174 (44%)

38 (10%)

3 (<1%)

Asthenia

122 (15%)

26 (3%)

54 (14%)

7 (2%)

1 (<1%)

Back pain

262 (33%)

53 (7%)

3 (<1%)

141 (36%)

39 (10%)

1 (<1%)

Nausea

258 (33%)

16 (2%)

1 (<1%)

130 (33%)

11 (3%)

Vomiting

191 (24%)

20 (3%)

1 (<1%)

101 (26%)

12 (3%)

Hematuria

73 (9%)

12 (2%)

34 (9%)

9 (2%)

Abdominal pain

102 (13%)

18 (2%)

47 (12%)

8 (2%)

Pain in extremity

156 (20%)

23 (3%)

1 (<1%)

82 (21%)

20 (5%)

Dyspnea

116 (15%)

12 (2%)

2 (<1%)

49 (12%)

7 (2%)

2 (<1%)

Constipation

223 (28%)

10 (1%)

126 (32%)

4 (1%)

Pyrexia

80 (10%)

3 (<1%)

36 (9%)

5 (1%)

Arthralgia

239 (30%)

40 (5%)

95 (24%)

17 (4%)

Urinary tract infection

105 (13%)

12 (2%)

29 (7%)

3 (<1%)

Pain

38 (5%)

7 (<1%)

21 (5%)

7 (2%)

1 (<1%)

Bone pain

216 (27%)

49 (6%)

2 (<1%)

117 (30%)

27 (7%)

4 (1%)

Adverse Events of Special Interest

Fluid retention or edema

261 (33%)

18 (2%)

2 (<1%)

94 (24%)

4 (1%)

Hypokalemia

143 (18%)

31 (4%)

4 (<1%)

36 (9%)

3 (<1%)

Cardiac disorders^✫

126 (16%)

32 (4%)

9 (1%)

46 (12%)

7 (2%)

2 (<1%)

Abnormalities in LFTs

89 (11%)

28 (4%)

2 (<1%)

35 (9%)

11 (3%)

3 (<1%)

Hypertension

88 (11%)

10 (1%)

32 (8%)

1 (<1%)

LFTs, Liver function tests

^✫Cardiac disorders associated with abiraterone acetate treatment as defined by the standardized Medical Dictionary for Regulatory Activities Queries included ischemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, cardiac failure, and possible arrhythmia-related investigations, signs, and symptoms

Treatment Monitoring

CBC before each cycle
Evaluation including PSA: Every 6 weeks
Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly
Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with abiraterone acetate, every 2 weeks for the first 3 months of treatment, and monthly thereafter. Modify, interrupt, or discontinue abiraterone acetate dosing as recommended
In patients with baseline moderate hepatic impairment receiving a reduced abiraterone acetate dose of 250 mg/day, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every 2 weeks for the following 2 months of treatment, and monthly, thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop
For patients who resume treatment after LFTs return to G ≤1 from a G2/3/4 toxicity, monitor serum transaminases and bilirubin at a minimum of every 2 weeks for 3 months and monthly thereafter
Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during, and after stressful situations

ADVANCED DISEASE REGIMEN: ENZALUTAMIDE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER—PRIOR CHEMOTHERAPY

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Advanced Disease Regimen: Enzalutamide Metastatic Castration-Resistant Prostate Cancer—Prior Chemotherapy

Scher HI et al. N Engl J Med 2012;367:1187–1197

Enzalutamide 160 mg orally, once daily, continually

Notes:

Can be taken with or without food
Swallow capsules whole. Do not chew, dissolve, or open the capsules

Notes:

If possible, avoid concomitant use of strong CYP2C8 inhibitors. If patients must receive a strong CYP2C8 inhibitor concomitantly, reduce the enzalutamide dose to 80 mg once daily. If coadministration of the strong inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of a strong CYP2C8 inhibitor
Coadministration of a strong CYP3A4 inhibitor (eg, itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers
The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo
Coadministration of enzalutamide with strong CYP3A4 inducers may decrease the plasma exposure of enzalutamide and should be avoided if possible
Moderate CYP3A4 inducers and St. John's wort may also reduce the plasma exposure of enzalutamide and should be avoided if possible
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4, CYP2C9 (eg, phenytoin, warfarin) and CYP2C19 should be avoided, as enzalutamide may decrease their exposure. If coadministration with warfarin cannot be avoided, conduct additional INR monitoring

Treatment Modification

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Treatment Modification

Adverse Event

Treatment Modification

G ≥3 adverse event or an intolerable side effect

Withhold dosing for 1 week or until symptoms improve to G ≤2, then resume at the same or a reduced dose (120 mg or 80 mg daily), if warranted

Occurrence of a seizure

Discontinue enzalutamide

Patient Population Studied

Patients had (a) a histologically or cytologically confirmed diagnosis of prostate cancer; (b) castrate levels of testosterone (<50 ng/dL; [<1.7 nmol/L]); (c) previous treatment with docetaxel; and (d) progressive disease defined according to Prostate Cancer Working Group 2 criteria (including 3 increasing values for PSA or radiographically confirmed progression with or without a rise in the PSA level)

Efficacy

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Efficacy

Multivariate Analysis of Hazard Ratios for Death^✫

Variable

Measurement Estimates

Hazard Ratio for Death (95% CI)^†

Coefficient

P Value

Study treatment (enzalutamide vs. placebo)

–0.54 ± 0.09

<0.001

0.58 (0.49–0.70)

ECOG performance score (0 or 1 vs. 2)

–0.33 ± 0.14

0.02

0.72 (0.55–0.95)

BPI-SF mean pain score (question no. 3) (<4 vs. ≥4)^‡

–0.23 ± 0.10

0.02

0.79 (0.65–0.97)

Progression at study entry (PSA only vs. radiographic)

–0.29 ± 0.09

0.002

0.75 (0.62–0.90)

Visceral disease at screening (no vs. yes)

–0.47 ± 0.10

<0.001

0.63 (0.52–0.76)

Secondary End Points Related to Response and Disease Progression^§

End Point

Enzalutamide (N = 800)

Placebo (N = 399)

Hazard Ratio (95% CI)

P Value

Confirmed PSA decline^§

≥1 Postbaseline PSA assessment—no. (%)

731 (91)

330 (83)

PSA response—no./total no. (%)

Decline ≥50% from baseline

395/731 (54)

5/330 (2)

<0.001

Decline ≥90% from baseline

181/731 (25)

3/330 (1)

<0.001

Soft-tissue objective response

Patients with measurable disease—no. (%)

446 (56)

208 (52)

CR or PR—no./total no. (%)

129/446 (29)

8/208 (4)

<0.001

FACT-P quality-of-life response^§

No (%) with ≥1 postbaseline assessment

651 (81)

257 (64)

Quality-of-life response—no./total no. (%)

281/651 (43)

47/257 (18)

<0.001

Progression indicators

Time to PSA progression

0.25 (0.20–0.30)

<0.001

Median, months

8.3

3.0

95% CI

5.8–8.3

2.9–3.7

Radiographic progression-free survival

0.40 (0.35–0.47)

<0.001

Median, months

8.3

2.9

95% CI

8.2–9.4

2.8–3.4

Time to first skeletal-related event

0.69 (0.57–0.84)

<0.001

Median, months

16.7

13.3

95% CI

14.6–19.1

9.9–NYR

BPI-SF, Brief Pain Inventory–Short Form; CI, confidence interval; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FACT-P, Functional Assessment of Cancer Therapy–Prostate; LDH, lactate dehydrogenase; NYR, not yet reached; PR, partial response

^✫Patients alive at the time of analysis were censored at the date patient was last known to be alive

^†Hazard ratios for death were calculated after adjustment for prognostic factors. These included age (<65 years vs. ≥65 years), region (North America vs. other), number of previous chemotherapy regimens (1 vs. 2), and baseline serum PSA level (per increase of 1 ng/mL). The Gleason score for prostate tumors was excluded owing to a large number of missing values

^‡On the Brief Pain Inventory–Short Form (BPI-SF) scores of 0–3 indicate clinically significant pain is absent and scores of 4–10 indicate clinically significant pain is present. Higher scores indicate greater pain

^§Only patients with both baseline and postbaseline assessments are included

Defined as 10-point improvement in the global score on the FACT-P questionnaire, as compared with baseline, on 2 consecutive measurements obtained at least 3 weeks apart

Toxicity

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Toxicity

Adverse Events, According to Grade

Adverse Event

Enzalutamide (N = 800)

Placebo (N = 399)

Any Grade

G ≥3

Any Grade

G ≥3

Number of Patients (Percent)

≥1 Adverse event

785 (98)

362 (45)

390 (98)

212 (53)

Any serious adverse event

268 (34)

227 (28)

154 (39)

134 (34)

Discontinuation owing to adverse event

61 (8)

37 (5)

39 (10)

28 (7)

Adverse event leading to death

23 (3)

14 (4)

Frequent adverse events more common with enzalutamide^✫

Fatigue

269 (34)

50 (6)

116 (29)

29 (7)

Diarrhea

171 (21)

9 (1)

70 (18)

1 (<1)

Hot flash

162 (20)

41 (10)

Musculoskeletal pain

109 (14)

8 (1)

40 (10)

1 (<1)

Headache

93 (12)

6 (<1)

22 (6)

Clinically significant adverse events

Cardiac disorder

Any

49 (6)

7 (1)

30 (8)

8 (2)

Myocardial infarction

2 (<1)

Abnormality on liver-function testing^†

8 (1)

3 (<1)

6 (2)

3 (<1)

Seizure

5 (<1)

^✫Includes adverse events that occurred in >10% of patients in the enzalutamide group and those that occurred in the enzalutamide group at a rate ≥2% higher than in the placebo group

^†Includes hyperbilirubinemia and increased levels of aspartate or alanine aminotransferases

Treatment Monitoring

Evaluation including PSA: Every 6 weeks

ADVANCED DISEASE REGIMEN: CABAZITAXEL + PREDNISONE

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Advanced Disease Regimen: Cabazitaxel + Prednisone

de Bono JS et al. Lancet 2010;376:1147–1154

Note: Severe hypersensitivity reactions can occur with cabazitaxel administration. These may include generalized rash/erythema, hypotension, and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of cabazitaxel infusion and administration of appropriate therapy. Patients should receive primary prophylaxis against hypersensitivity reactions as described below. Cabazitaxel must not be given to patients who have a history of severe hypersensitivity reactions to other drugs formulated with polysorbate 80, such as fosaprepitant dimeglumine (the parenteral formulation of aprepitant [Emend]), darbepoetin alfa, docetaxel, etoposide, recombinant human papillomavirus quadrivalent vaccine (Gardasil), and various vaccines. Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the cabazitaxel infusion, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available

Premedication:

At least 30 minutes prior to each cabazitaxel dose, administer the following medications to reduce the risk and/or severity of hypersensitivity:

Diphenhydramine 25 mg, or an equivalent H₁-receptor antihistamine, orally or intravenously
Dexamethasone 8 mg or an equipotent glucocorticoid
Ranitidine 50 mg intravenously or 150 mg orally, or an equivalent histamine (H₂)-receptor antagonist

Cabazitaxel 25 mg/m² intravenously over 60 minutes, diluted in a volume of 0.9% sodium chloride injection or 5% dextrose injection sufficient to produce a solution with concentration within the range 0.1–0.26 mg/mL, on day 1, every 3 weeks (total dosage/cycle = 25 mg/m²)

Prednisone 10 mg/day orally, continually for 21 consecutive days (total dose/21-day cycle = 210 mg)

Note:

Cabazitaxel is extensively metabolized in the liver (>95%), primarily by cytochrome P450 (CYP) CYP3A4/5 enzymes (80–90%), and, to a lesser extent, by the polymorphically expressed enzyme, CYP2C8. Consequently hepatic impairment is likely to increase cabazitaxel concentrations
Although no formal drug interaction trials with cabazitaxel have been conducted, clinicians should use caution with respect to the following:
- CYP3A4 inhibitors: Concomitant administration of strong CYP3A subfamily inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) is expected to increase concentrations of cabazitaxel. Therefore, coadministration with strong CYP3A inhibitors should be avoided. Caution should be exercised with concomitant use of moderate CYP3A subfamily inhibitors
- CYP3A4 inducers: The concomitant administration of strong CYP3A subfamily inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifapentine, rifampin) is expected to decrease cabazitaxel concentrations. Therefore, coadministration with strong CYP3A inducers should be avoided. In addition, patients should also refrain from taking St. John's wort

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Prolonged grade ≥3 neutropenia (>1 week) despite appropriate medication including filgrastim

Delay treatment until neutrophil count is >1500 cells/mm³, then reduce cabazitaxel dosage to 20 mg/m². Use filgrastim for secondary prophylaxis

Prolonged grade ≥3 neutropenia (>1 week) despite appropriate medication including filgrastim at a cabazitaxel dosage of 20 mg/m²

Discontinue cabazitaxel

Febrile neutropenia

Delay treatment until improvement or resolution, and until neutrophil count is >1500 cells/mm³, then resume treatment with cabazitaxel dosage decreased to 20 mg/m². Use filgrastim for secondary prophylaxis

Febrile neutropenia at a cabazitaxel dosage of 20 mg/m²

Discontinue cabazitaxel

Grade ≥3 diarrhea or diarrhea that persists despite appropriate medication, fluid, and electrolytes replacement

Delay treatment until improvement or resolution, then resume treatment with cabazitaxel dosage decreased to 20 mg/m²

Grade ≥3 diarrhea or diarrhea that persists despite appropriate medication, fluid, and electrolytes replacement at a cabazitaxel dosage of 20 mg/m²

Discontinue cabazitaxel

Total bilirubin ≥ ULN, or AST and/or ALT ≥1.5 times ULN)

Discontinue cabazitaxel

Toxicity (N = 371)

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Toxicity^✫ (N = 371)

% All Grades

% G ≥3

Hematologic

Neutropenia

Febrile neutropenia

—

Leukopenia

Anemia

Thrombocytopenia

Nonhematologic

Diarrhea

Fatigue

Asthenia

Back pain

Nausea

Vomiting

Hematuria

Abdominal pain

Pain in extremity

Dyspnea

Constipation

Pyrexia

Arthralgia

Urinary tract infection

Pain

Bone pain

^✫NCI Common Terminology Criteria for Adverse Events, version 3

Efficacy

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Efficacy

Mitoxantrone

Cabazitaxel

p-Value

Tumor Response Rate^✫

Number of evaluable patients

204

201

Response rate (%)

4.4%

14.4%

0.0005

PSA Response Rate^†

Number of evaluable patients

325

329

Response rate (%)

17.8%

39.2%

0.0002

Pain Response Rate^‡

Number of evaluable patients

168

174

Response rate (%)

7.7%

9.2%

0.63

Progression

Number pts in intention-to-treat analysis

377

378

Median time to tumor progression (months)

5.4

8.8

<0.0001

Median time to PSA progression (months)

3.1

6.4

0.001

Median time to pain progression (months)^§

11.1 (2.9-NR)

0.52

NR, Not reached

^✫Tumor response was evaluated only for patients with measurable disease according to RECIST

^†PSA response was defined as ≥50% reduction in serum PSA concentrations, established only for patients with a serum PSA concentration of 20 mcg/L or more at baseline, confirmed by a repeat PSA measurement after at least 3 weeks

^‡Pain response was established only for patients with a median present pain intensity (PPI) score ≥2, a mean analgesic score (AS) ≥10 points at baseline, or both, and was defined as a reduction from baseline median PPI score ≥2 points without an increased AS or a decrease ≥50% in the AS without an increase in the PPI score, maintained for at least 3 weeks

^§Data for 265 patients in the cabazitaxel group and 279 patients in the mitoxantrone group were censored as a result of ≥2 PPI or AS assessments or both, being missed during the same week (unless a complete evaluation of ≥5 values showed pain progression)

Patient Population Studied

A study of 755 patients with pathologically proven castration-refractory prostate cancer with documented disease progression during or after completion of docetaxel treatment. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0–2. Patients with measurable disease were required to have documented disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) criteria with at least 1 metastatic visceral or soft-tissue lesion. Patients with nonmeasurable disease were required to have rising serum prostate-specific antigen (PSA) concentrations (at least 2 consecutive increases relative to a reference value measured at least a week apart) or the appearance of at least 1 new demonstrable radiographic lesion. Additional inclusion criteria were: previous and ongoing castration by orchiectomy, LHRH agonists, or both interventions

Therapy Monitoring

Before each cycle: Physical exam, CBC and LFTs
Evaluation including PSA: Every 6 weeks to every 3 months

ADVANCED DISEASE REGIMEN: KETOCONAZOLE + HYDROCORTISONE

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Advanced Disease Regimen: Ketoconazole + Hydrocortisone

Bok RA, Small EJ. Drug Saf 1999;20:451–458

Small EJ et al. J Urol 1997;157:1204–1207

Ketoconazole 400 mg orally every 8 hours, continually

Hydrocortisone 20 mg orally every morning, continually

Hydrocortisone 10 mg orally every evening, continually

Notes:

Ketoconazole absorption can be decreased with concurrent use of antacids, H₂-antagonist antihistamines, and proton pump inhibitors (PPIs). Avoid H₂-antagonists and PPIs. If antacid treatment is needed, ketoconazole should be taken at least 2 hours before antacids
To avoid nausea, start ketoconazole at a low dose (eg, 200 mg 3 times daily) and gradually increase to full doses after several days

Supportive Care

Antiemetic prophylaxis

The regimen is not emetogenic. Primary prophylaxis is not indicated

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A study of 48 patients with castration-refractory metastatic prostate cancer with progression after antiandrogen withdrawal

Efficacy

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Efficacy

>50% PSA decline (≥8 weeks)

62.5%

Median change in PSA

79.5% decline

Mean duration of response

3.5 months

Small EJ et al. J Urol 1997;157:1204–1207

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Toxicity G ≥2

Hold ketoconazole until adverse events have resolved

Note: Ketoconazole is a potent inhibitor of the cytochrome P450 enzyme, CYP3A4. It has been reported to inhibit the metabolism of many drugs and drug metabolites that are metabolized by CYP3A-subfamily enzymes, resulting in elevated concentrations of the drugs. Affected drugs include (but are not limited to):

Warfarin (enhances anticoagulant effect)
Dihydropyridine calcium channel antagonists (eg, amlodipine, felodipine, nifedipine)
Loratadine
Some HIV protease inhibitors (saquinavir, indinavir and nelfinavir)
Statin hypolipidemic drugs (HMG-CoA reductase inhibitors)
Many other drugs and natural products

Drugs that are susceptible to pharmacokinetic interactions because of concomitant use with ketoconazole may require dose or schedule adjustments. It may be prudent to consider alternative treatment options, or if clinically appropriate, discontinue drugs that are known to interact with ketoconazole

Therapy Monitoring

Monthly: LFTs including AST, ALT, bilirubin, alkaline phosphatase, PSA if indicated

Notes

Liver transaminases may be transiently increased. Therapy can be continued in a setting of a grade 1 increase in transaminases with close monitoring, but there is a small risk (0.1–1%) of idiosyncratic hepatitis, which can be fatal
Some clinicians administer higher doses of hydrocortisone (30 mg in the morning and 20 mg in the evening)
In addition to glucocorticoid replacement, some patients require mineralocorticoid supplementation with fludrocortisone 100–200 mcg daily orally in the morning

Toxicity (N = Varies)

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Toxicity (N = Varies)

% Patients

Mild (G1/2)

Moderate/Severe

Nausea/vomiting

—

LFT abnormalities^✫

4-20

—

Fulminant hepatitis

—

0.1-1

Fatigue

—

Edema

—

"Sticky skin"^†,‡

—

Rash^‡

—

Nail dystrophy^‡

Common

—

Dry mouth^‡

Often

—

Gynecomastia^§

10-15

—

Adrenal insufficiency

Varies

Impotence

Anticipated

^✫Asymptomatic increases; usually resolve with discontinuation of treatment

^†Subjective sensation of stickiness to the skin, usually noted in axillary area

^‡Cutaneous and mucosal effects probably related to inhibitory effect on retinoic acid metabolism

^§Not observed with ketoconazole 200–400 mg/day, but may occur with higher doses

Steroid replacement recommended

From Bok RA, Small EJ. Drug Saf 1999;20:451–458

ADVANCED DISEASE REGIMEN: RADIUM-223 METASTATIC CASTRATION-RESISTANT PROSTATE CANCER WITH BONE METASTASES

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Advanced Disease Regimen: Radium-223 Metastatic Castration-Resistant Prostate Cancer with Bone Metastases

Parker et al. N Engl J Med 2013;369:213–223

XOFIGO (radium 223) Package Insert (http://labeling.bayerhealthcare.com/html/products/pi/Xofigo_PI.pdf)

Radium (Ra)-223 dichloride 50 kBq (²²³Ra 1.35 μCi) per kilogram of body weight by slow intravenous injection over 1 minute every 4 weeks for 6 injections

Note:

Flush the intravenous access line or cannula with 0.9% sodium chloride injection before and after injection of radium-223
Safety and efficacy beyond 6 injections with radium-223 have not been studied

Calculate volume to be administered to a given patient using the:

Patient's body weight (kg)
Dosage level 50 kBq/kg body weight or 1.35 μCi/kg body weight
Radioactivity concentration of the product (1000 kBq/mL; 27 μCi/mL) at the reference date
Decay correction factor to correct for physical decay of radium-223

Calculate total volume to be administered as follows:

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Decay Correction Factor Table

Days from Reference Date

Decay Factor

Days from Reference Date

Decay Factor

–14

2.296

0.982

–13

2.161

0.925

–12

2.034

0.870

–11

1.914

0.819

–10

1.802

0.771

–9

1.696

0.725

–8

1.596

0.683

–7

1.502

0.643

–6

1.414

0.605

–5

1.330

0.569

–4

1.252

0.536

–3

1.178

0.504

–2

1.109

0.475

–1

1.044

0.447

0.420

The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To determine the decay correction factor, count the number before or after the reference date. The Decay Correction Factor Table includes a correction to account for the 7-hour time difference between 12 noon European Time (CET) at the site of manufacture and 12 noon U.S. CST, which is 7 hours earlier than CET

Note: Immediately before and after administration, the net patient dose of administered radium-223 should be determined by measurement in an appropriate radioisotope dose calibrator that has been calibrated with a National Institute of Standards and Technology (NIST) traceable radium-223 standard and corrected for decay using the date and time of calibration

Safety Information: Radium-223 is primarily an alpha emitter, with 95.3% of energy emitted as alpha particles. Only 3.6% is emitted as beta particles and 1.1% as gamma radiation. Thus the external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be <8000 kBq (<216 μCi). Nevertheless care should be used as follows:

Precautions:

The administration of radium-223 is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations
Whenever possible, patients should use a toilet (commode) and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with radium-223 or patient fecal matter or urine should be washed promptly and separately from other clothing

Instructions to Patients:

Stay well hydrated and monitor oral intake, fluid status, and urine output. Report signs of dehydration
There are no restrictions regarding contact with other people after receiving radium-223. Follow good hygiene practices for at least 1 week after the last injection so as to minimize radiation exposure from bodily fluids to household members and caregivers
Flush toilets several times after each use
Promptly wash clothing soiled with fecal matter or urine separately from other clothing
Caregivers should use universal precautions when handling body fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers
Patients who are sexually active should use condoms and their female partners of reproductive potential should use a highly effective method of birth control during treatment and for 6 months following completion of radium-223 treatment

Toxicity

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Toxicity

Adverse Events That Occurred in at Least 5% of Patients in Either Study Group in the Safety Population^✫

Adverse Event

Radium-223 (N = 600)

Placebo (N = 301)

% All Grades

% G3

% G4

% G5

% All Grades

% G3

% G4

% G5

Hematologic

Anemia

Thrombocytopenia

Neutropenia

Nonhematologic

Constipation

Diarrhea

Nausea

Vomiting

Asthenia

Fatigue

Deterioration general physical health

Peripheral edema

Pyrexia

Pneumonia

Urinary tract infection

Weight loss

Anorexia

Decreased appetite

Bone pain

Muscular weakness

Pathologic fracture

Progression malignant neoplasm

Dizziness

Spinal cord compression

Insomnia

Hematuria

Urinary retention

Dyspnea

^✫Only 1 G5 hematologic adverse event was considered possibly related to study drug: thrombocytopenia in 1 patient in the radium-223 group

Patient Population Studied

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Patient Population Studied

Inclusion criteria: (a) histologically confirmed, progressive castration-resistant prostate cancer (b) 2 or more bone metastases detected on skeletal scintigraphy and no known visceral metastases; (c) received docetaxel, or were not healthy enough or declined to receive it, or it was not available; (d) symptomatic disease with regular use of analgesic medication or treatment with external beam radiation therapy required for cancer-related bone pain within the previous 12 weeks; (e) a baseline PSA ≥5 ng/mL or with evidence of progressively increasing PSA values (2 consecutive increases over the previous reference value); (f ) an ECOG performance-status score of 0–2; and (g) a life expectancy ≥6 months. Exclusion criteria: (a) chemotherapy within the previous 4 weeks; (b) previous hemibody external radiotherapy; (c) systemic radiotherapy with radioisotopes within the previous 24 weeks; (d) a blood transfusion or use of erythropoietin-stimulating agents within the previous 4 weeks; (e) malignant lymphadenopathy ≥3 cm in the short-axis diameter; (f ) history of or the presence of visceral metastases; and (g) imminent or established spinal cord compression

Castration-resistant disease was defined as a serum testosterone level ≤50 ng/dL (≤1.7 nmol/L) after bilateral orchiectomy or during maintenance treatment consisting of androgen-ablation therapy with a luteinizing hormone-releasing hormone agonist or polyestradiol phosphate. Patients with castration-resistant disease during maintenance treatment were required to continue that treatment throughout the study

Baseline Characteristics of the Patients^✫

Characteristic

Radium-223 (N = 614)

Placebo (N = 307)

Age

Median (range)—years

71 (49–90)

71 (44–94)

>75 years—no. (%)

171 (28)

90 (29)

Total alkaline phosphatase—no. (%)

<220 U/L

348 (57)

169 (55)

≥220 U/L

266 (43)

138 (45)

Current use of bisphosphonates—no. (%)

Yes

250 (41)

124 (40)

364 (59)

183 (60)

Any previous use of docetaxel—no. (%)

Yes

352 (57)

174 (57)

262 (43)

133 (43)

ECOG performance-status score—no. (%)

165 (27)

78 (25)

371 (60)

187 (61)

≥2

77 (13)

41 (13)

WHO ladder for cancer pain—no. (%)^†

1 (mild pain/no opioid use)

257 (42)

137 (45)

2 (moderate pain/occasional opioid use)

151 (25)

78 (25)

3 (severe pain/regular daily opioid use)

194 (32)

90 (29)

Extent of disease—no. (%)

<6 metastases

100 (16)

38 (12)

6–20 metastases

262 (43)

147 (48)

>20 metastases

195 (32)

91 (30)

Superscan^‡

54 (9)

30 (10)

External beam radiation therapy within 12 weeks after screening—no. (%)

Yes

99 (16)

48 (16)

515 (84)

259 (84)

Median biochemical values (Range)

Hemoglobin (normal range = 13.4–17.0 g/dL)

12.2 (8.5–15.7)

12.1 (8.5–16.4)

Albumin (normal range: 36–45 g/L)

40 (24–53)

40 (23–50)

Total alkaline phosphatase >105 U/L

211 (32–6431)

223 (29–4805)

Lactate dehydrogenase >255 U/L

315 (76–2171)

336 (132–3856)

PSA >3.999 ng/mL

146 (3.8–6026)

173 (1.5–14500)

ECOG, Eastern Cooperative Oncology Group

^✫Percentages may not sum to 100 due to rounding

^†A total of 12 patients in the radium-223 group (2%) and 2 patients in the placebo group (1%) had no pain or analgesic use at baseline

^‡Superscan refers to a bone scan showing diffuse, intense skeletal uptake of the tracer without renal and background activity

Treatment Modifications

None

Treatment Monitoring

Weekly CBC with differential and platelet count
Monitor oral intake, fluid status, and urine output during treatment with radium-223
- Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure or insufficiency

Efficacy

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Efficacy

Overall Survival and Subgroup Analyses of Hazard Ratios for Death

End Point

Radium-223 (N = 614)

Placebo (N = 307)

Hazard Ratio (95% CI)

P Value

Median overall survival, months

14.9

11.3

0.70 (0.58–0.83)

<0.001

Total AP at baseline

<220 U/L

—

0.82 (0.64–1.07)

—

≥220 U/L

—

0.62 (0.49–0.79)

—

Current bisphosphonate use

Yes

—

0.70 (0.52–0.93)

—

0.74 (0.59–0.92)

—

Previous docetaxel use

Yes

—

0.71 (0.56–0.89)

—

0.74 (0.56–0.99)

—

ECOG performance-status score

0 or 1

—

0.68 (0.56–0.82)

—

≥2

—

0.82 (0.50–1.35)

—

Extent of disease

<6 metastases

—

0.95 (0.46–1.95)

—

6–20 metastases

—

0.71 (0.54–0.92)

—

>20 metastases

—

0.64 (0.47–0.88)

—

Superscan^✫

—

0.71 (0.40–1.27)

—

Opioid use

Yes

—

0.68 (0.54–0.86)

—

0.70 (0.52–0.93)

—

Main Secondary Efficacy End Points in the Intention-to-Treat Population

End Point

Radium-223 (N = 614)

Placebo (N = 307)

Hazard Ratio (95% CI)

P Value

Median time to first symptomatic skeletal event

15.6 mo

9.8 mo

0.66 (0.52–0.83)

<0.001

Median time to increase in total alkaline phosphatase

7.4 mo

3.8 mo

0.17 (0.13–0.22)

<0.001

Median time to increase in PSA level

3.6 mo

3.4 mo

0.64 (0.54–0.77)

<0.001

≥30% reduction in total alkaline phosphatase

233/497 (47)

7/211 (3)

—

<0.001

Normalization of total alkaline phosphatase

109/321 (34)

2/140 (1)

—

<0.001

^✫Superscan refers to a bone scan showing diffuse, intense skeletal uptake of the tracer without renal and background activity

REGIMENS: HORMONAL AGENTS

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Regimens: Hormonal Agents

Bolla M et al. Lancet 2002;360:103–108

Delaere KPJ, Van Thillo EL. Semin Oncol 1991;18(5 Suppl 6):13–18

Iversen P et al. J Urol 2000;164:1579–1582

Janknegt RA. Cancer 1993;72(12 Suppl 17):3874–3877

Janknegt RA et al. J Urol 1993;149:77–83

Periti P et al. Clin Pharmacokinet 2002;41:485–504

Tyrrell CJ. Eur Urol 1994;26(Suppl 1):15–19

Treatment options:

Surgical castration: Orchiectomy
Medical castration: LHRH agonists
Nonsteroidal antiandrogens
Androgen-deprivation therapy (ADT)
- GnRH antagonist
- Orchiectomy + antiandrogen
- LHRH agonist + antiandrogen

LHRH agonists:

Leuprolide depot 7.5 mg intramuscularly every month
Leuprolide depot 22.5 mg intramuscularly every 3 months
Leuprolide depot 30 mg intramuscularly every 4 months
Leuprolide depot 45 mg intramuscularly every 6 months
Goserelin implant 3.6 mg subcutaneously every 4 weeks
Goserelin implant 10.8 mg subcutaneously every 3 months

Nonsteroidal antiandrogens:

Flutamide 250 mg/dose orally 3 times per day, continually
Bicalutamide 50 mg or 150 mg/day if given as monotherapy orally, continually
Nilutamide 300 mg/day orally for 1 month with castration, followed by nilutamide 150 mg/day orally, continually

GnRH antagonist

Degarelix, starting dose, 240 mg given as two subcutaneous injections of 120 mg in the first month followed by maintenance dose of 80 mg given as one subcutaneous injection monthly thereafter

Supportive Care

Antiemetic prophylaxis

The regimens are not emetogenic. Primary prophylaxis is not indicated

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Efficacy

Metastatic disease

LHRH agonists ≤85% response rate
No significant differences among LHRH agonists
Single-agent antiandrogen therapy may be inferior to medical (LHRH agonist) or surgical castration
Use of combined androgen blockade (CAB) as frontline therapy is controversial with limited evidence of clinical benefit

Locally advanced disease

Concurrent radiation and hormonal therapy in locally advanced disease appears to have a survival benefit. LHRH agonist + an antiandrogen are used for up to 3 months before, during, and for 3 years after radiation treatment

Bolla M et al. Lancet 2002;360:103–108

Laverdière J et al. Int J Radiat Oncol Biol Phys 1997;37:247–252

Prostate Cancer Trialists' Collaborative Group. Lancet 2000;355:1491–1498

Seidenfeld J et al. Ann Intern Med 2000;132:566–577.

Erratum in: Ann Intern Med 2005;143:764–765; comment in: Ann Intern Med 2000;132:584–585

Patient Population Studied

Patients with metastatic and locally advanced prostate cancer treated with hormonal therapy

Therapy Monitoring

All antiandrogens

Monthly for the first 4 months: LFTs
Every 2–3 months after the first 4 months: LFTs

Nilutamide

Baseline chest x-ray before therapy
For respiratory symptoms: Discontinue therapy pending evaluation

Wysowski DK, Fourcroy JL. J Urol 1996;155:209–212

Toxicity

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Toxicity

Common Toxicities of Androgen Deprivation

Hot flashes

LHRH Ag > AA

Loss of libido, impotence

LHRH Ag >> AA

Bone and muscle loss

LHRH Ag >> AA

Breast tenderness

AA >> LHRH Ag

Gynecomastia

AA >> LHRH Ag

Skin and hair changes

N/A

Weight gain

N/A

Asthenia

N/A

AA, antiandrogens; LHRH Ag, LHRH agonists

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Toxicity

Toxicities of Individual Androgen Therapies

% Patients

LHRH Agonists

Tumor flare

Variable

Injection-site reactions

Variable

Flutamide

Gynecomastia

45-50

Diarrhea

Nausea/vomiting

Hepatitis

2.5

Vertigo

2.5

Hot flashes

2.5

Bicalutamide

Gynecomastia

Breast tenderness

Constipation

Aggravation reaction

Hot flashes

Asthenia

Urinary retention

Diarrhea

Nausea/vomiting

Nilutamide

Hot flashes

Visual disturbance^✫

27-50

Nausea

10 (7-20)

Dyspnea

Interstitial pneumonitis

1-2

Gynecomastia

Alcohol intolerance

5-19

Increased LFTs^†

4-8

Anemia

^✫Includes decreased adaptation to darkness, blurred vision

^†Transient in a majority of patients

Notes

For patients with metastatic prostate cancer being treated with an LHRH agonist alone, a testosterone level should be checked at 1 month. If it is >20 ng/dL, consider orchiectomy or adding antiandrogen
Concurrent antiandrogen therapy can be used with LHRH agonist for the first 2–4 weeks of treatment to avoid tumor flare
Antiandrogen withdrawal should be considered the first therapeutic maneuver in men whose disease has progressed after treatment with combined androgen blockade. Approximately 20% of patients have a significant decrease in serum PSA when antiandrogen is withdrawn
Degarelix binds to the GnRH receptor in the pituitary gland and blocks LH/FSH release from the pituitary. Patients typically achieve castrate levels of testosterone by day 3 of treatment without a testosterone surge. A Phase 3, one year multicenter, randomized, open-label trial compared the efficacy and safety of degarelix with leuprolide. Six-hundred and ten patients with all stages of histologically confirmed prostate cancer for whom androgen deprivation therapy was indicated were enrolled. Patients receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (p = 0.05). PSA recurrences occurred primarily in patients with advanced disease and exclusively in those with baseline PSA >20 ng/mL. The latter had a significantly longer time to PSA recurrence with degarelix. The results suggest degarelix offers improved PSA control compared with leuprolide. However, further studies are warranted to confirm these findings
With acute cord compression or other oncologic emergency caused by a growing prostate tumor, Degarelix is the preferred treatment

Kelly WK, Scher HI. J Urol 1993;149:607–609

Pont A. J Urol 1987;137:902–904

Tombal et al. Eur Urol 2010;57:836–842

IMMUNOTHERAPY REGIMEN: SIPULEUCEL-T

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Immunotherapy Regimen: Sipuleucel-T

Kantoff PW et al. N Engl J Med 2010;363:411–422

General notes:

Patients are scheduled for 3 leukapheresis procedures (at weeks 0, 2, and 4), each followed approximately 3 days later by infusion of sipuleucel-T
Infusions are prepared from PBMCs collected by means of a single standard leukapheresis processing 1.5 to 2 times a patient's estimated blood volume
Sipuleucel-T is prepared at a designated manufacturing facility by culturing APCs for 36–44 hours at 37°C (98.6°F) with media containing PA2024. The cells are washed before final formulation

Premedication:

Acetaminophen 650 mg orally approximately 30 minutes prior to the administration of sipuleucel-T, and

Diphenhydramine 25–50 mg, or an equivalent H₁-receptor antihistamine orally approximately 30 minutes prior to the administration of sipuleucel-T

Sipuleucel-T suspension for intravenous infusion containing a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF/dose in 250 mL lactated Ringer injection, intravenously over a period of approximately 60 minutes. Administer a total of 3 doses at approximately 2-week intervals (total dose/single treatment is at least 50 million autologous CD54+ cells activated with PAP-GM-CSF)

Notes for acute infusion reactions: Interrupt or slow infusion depending on the severity of the reaction. Administer appropriate medical therapy including:

Diphenhydramine 25–50 mg, or an equivalent H₁-receptor antihistamine, intravenously
Ranitidine 50 mg, cimetidine 300 mg, famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist, intravenously over 15–30 minutes
Note: In healthy subjects, cimetidine reduces the clearance and volume of distribution of meperidine; thus, use caution when these drugs are used concomitantly
Meperidine 10–25 mg intravenously as needed for chills

Important:

Sipuleucel-T is for autologous use only. Before infusion, confirm that a patient's identity matches patient identifiers on the infusion containers
Do not initiate infusion of expired sipuleucel-T. If, for any reason, a patient is unable to receive a scheduled infusion of sipuleucel-T, the patient will need to undergo an additional leukapheresis procedure if the course of treatment is to be continued. Patients should be advised of this possibility prior to initiating treatment
The sipuleucel-T infusion bag must remain within its insulated polyurethane container until the time of administration. Do not remove the insulated polyurethane container from its outer cardboard shipping box
DO NOT USE a cell filter to administer sipuleucel-T

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

Adverse Event

Dose Modification

Acute infusion reactions

Interrupt or slow infusion depending on the severity of the reaction and administer appropriate medical therapy including intravenous H₁/H₂ antagonists ± low-dose meperidine

Patient Population Studied

A study of 512 patients with metastatic castration-resistant prostate cancer and an expected survival ≥6 months (341 randomized to sipuleucel-T and 171 to placebo). Initially, only men without disease-related symptoms and a Gleason score ≤7 were enrolled. Eligibility criteria were later amended to include men with any Gleason score, as well as those with minimal disease-related symptoms. Additional eligibility criteria were a serum PSA ≥5 mcg/L, a serum testosterone level <50 ng/dL (<1.7 nmol/L), and progressive disease on the basis of imaging studies or PSA measurements. Exclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status ≥2, visceral metastases, pathologic long-bone fractures, spinal cord compression, and treatment within the previous 28 days with systemic glucocorticoids, external beam radiation, surgery, or systemic therapy for prostate cancer (except medical or surgical castration). Patients were also excluded if they had undergone chemotherapy within the previous 3 months. Continuation of medical castration or bisphosphonate therapy was required at least until the time of disease progression

Efficacy

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Efficacy^✫

Median time to objective disease progression

14.6 weeks^†

Adjusted HR for death, sipuleucel-T vs. placebo

0.78 (95% CI, 0.61–0.98)

Median overall survival

25.8 months^‡

Estimated probability of survival at 36 months

31.7%^§

Reductions of PSA ≥50% on two visits ≥4 weeks apart

2.6%

Antibody titers against the immunizing antigen, PA2024 ≤400 at any time after baseline

66.2%^✫^✫^{,‡ ‡}

Antibodies titers against prostatic acid phosphatase >400 at any time after baseline

28.5%^{† †,‡ ‡}

^✫Median follow up time: 34.1 months

^†Placebo group: 14.4 weeks

^‡Placebo group: 21.7 months

^§Placebo group: 23%

Placebo group: 1.3%

^✫^✫Placebo group: 2.9%

^††Placebo group: 1.4%

^‡‡In prespecified analyses, patients in the sipuleucel-T group who had an antibody titer >400 against PA2024 or prostatic acid phosphatase at any time after baseline lived longer than those who had an antibody titer ≤400 (P <0.001 and P = 0.08, respectively, by the log-rank test)

Therapy Monitoring

Before each cycle: CBC with LFTs
Evaluation including PSA: Every 6 weeks

Toxicity

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Toxicity^✫

Toxicity

Sipuleucel-T (N = 338)

Placebo (N = 168)

% All Grades

% G3/4/5

% All Grades

% G3/4/5

Any

98.8

31.7

96.4

35.1

Chills

54.1

1.2

12.5

Fatigue

39.1

1.1

38.1

1.8

Back pain

34.3

3.6

36.3

4.8

Pyrexia

29.3

0.3

13.7

1.8

Nausea

28.1

0.6

20.8

Arthralgia

20.7

2.1

23.8

3.0

Citrate toxicity^†

20.1

20.2

Vomiting

17.8

11.9

Headache

16.0

0.3

4.8

Dizziness

14.5

9.5

Pain

13.0

1.8

7.1

1.2

Influenza-like illness

9.8

3.6

Bone pain

9.5

0.9

10.7

1.2

Hypertension

7.4

0.6

3.0

Anorexia

7.1

0.3

16.1

1.8

Weight loss

5.9

0.6

10.7

0.6

Hyperhidrosis

5.3

0.6

Groin pain

5.0

2.4

Anxiety

3.8

8.3

Flank pain

2.7

6.0

Depression

2.4

0.3

6.5

% Mild/Moderate (G1/2)

% Severe (G3)^§

Acute infusion reactions^‡

67.7

3.5

^✫NCI Common Terminology Criteria for Adverse Events, version 3

^†Citrate toxicity has been associated with leukapheresis; paresthesia and oral paresthesia are likely symptoms of citrate toxicity

^‡Acute infusion reactions (reported within 1 day after infusion) included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, tachycardia, muscle ache, nausea, and vomiting. The most common events (≥20%) were chills, fever, and fatigue. Fevers and chills generally resolved within 2 days (71.9% and 89.0%, respectively)

^§The incidence of severe events was greater following the second sipuleucel-T infusion in comparison with the first infusion (2.1% vs. 0.8%, respectively), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the sipuleucel-T group were hospitalized within 1 day after infusion for management of acute infusion reactions. No G4/5 acute infusion reactions were reported with sipuleucel-T

PROSTATE CANCER REGIMEN: ENZALUTAMIDE (BEFORE CHEMOTHERAPY)

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Prostate Cancer Regimen: Enzalutamide (Before Chemotherapy)

Beer TM et al. N Engl J Med 2014;371:424-433.

Comment in: Nat Rev Urol. 2014;11:361. N Engl J Med. 2014;371:1755-1756. Eur Urol 2014;66:785-786. Asian J Androl 2014;16:803-804, 807-808. Eur Urol 2015;67:174. Cancer Biol Ther 2015;16:201-203

Protocol for: Beer TM et al. N Engl J Med 2014;371:424-433.

Supplementary appendix to: Beer TM et al. N Engl J Med 2014;371:424-433.

Enzalutamide 160 mg per dose; administer orally once daily at about the same time each day either with or without food, continually (total dose/week = 1120 mg)

Notes:

Patients receiving enzalutamide should have undergone bilateral orchiectomy or should also receive concurrent treatment with a gonadotropin-releasing hormone (GnRH) analogue or GnRH antagonist.
Coadministration of a strong CYP2C8 inhibitor (eg, gemfibrozil) increased the composite area under the curve (AUC) of enzalutamide plus N -desmethyl enzalutamide by 2.2-fold in healthy volunteers. If possible, avoid concomitant use of strong CYP2C8 inhibitors. If patients must receive a strong CYP2C8 inhibitor concomitantly, reduce the enzalutamide dose to 80 mg once daily. If coadministration of the strong inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of a strong CYP2C8 inhibitor
Coadministration of a strong CYP3A4 inhibitor (eg, itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers
Coadministration of enzalutamide with rifampin (a strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide pus N-desmethyl enzalutamide by 37%. Coadministration of enzalutamide with strong CYP3A4 inducers and St John's wort should be avoided if possible. If coadministration of a strong CYP3A4 inducer with enzalutamide is required, increase the dosage of enzalutamide from 160 mg by mouth once daily to 240 mg by mouth once daily
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4, CYP2C9 (eg, phenytoin, warfarin), and CYP2C19 should be avoided, as enzalutamide may decrease their exposure. If coadministration with warfarin cannot be avoided, conduct additional INR monitoring

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Patient Population Studied

An international, multicenter, randomized, double-blind, phase 3 trial (PREVAIL) involved 1717 patients with histologically or cytologically confirmed adenocarcinoma of the prostrate. Eligible patients had documented metastases, prostate-specific antigen, and/or radiographic progression in bone or soft tissue despite receiving luteinizing hormone-releasing hormone analogue therapy or undergoing orchiectomy; serum testosterone level ≤1.73 nmol/L, Eastern Cooperative Oncology Group (ECOG) performance status ≤1, and Brief Pain Inventory Short Form question 3 score ≤3, and had to be on continued androgen-deprivation therapy. Patients who had received cytotoxic chemotherapy, ketoconazole, or abiraterone acetate, or who had a history of seizure or a condition that could confer a predisposition to seizure, were not eligible. Patients were randomly assigned to receive oral enzalutamide 160 mg or placebo once daily

Efficacy (N = 1717)

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Efficacy (N = 1717)

Median overall survival^✫

32.4 months with enzalutamide

30.2 months with placebo

HR for death 0.71, 95% CI 0.60-0.84, P <0.001

Radiographic progression-free survival at 12 months

65% with enzalutamide

14% with placebo

HR for radiographic progression or death 0.19, 95% CI 0.15-0.23, P <0.001

^✫Estimated at the planned interim analysis, when median duration of follow-up for survival was ~22 months.

Therapy Monitoring

Obtain CBC with differential prior to start of therapy
Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia
Monitor blood pressure at least monthly. Encourage patients to monitor their blood pressure
Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents
Advise patients who have a history of seizure of the risk of developing a seizure and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others
Obtain serum PSA at every visit; monitor radiographic imaging every 3 months initially and then every 4 months in patients with radiographically evaluable disease

Treatment Modifications

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Treatment Modifications

ENZALUTAMIDE

Starting dose

160 mg by mouth once daily

Dose level −1

120 mg by mouth once daily

Dose level −2

80 mg by mouth once daily

Dose level −3

Discontinue therapy

General Dosage Adjustments

Seizure

Permanently discontinue enzalutamide

Posterior reversible encephalopathy syndrome (PRES)

Permanently discontinue enzalutamide

Hypersensitivity to enzalutamide

Permanently discontinue enzalutamide

≤G2 ischemic heart disease event

Continue enzalutamide at current dosage and optimize management of cardiovascular risk factors

G3/4 ischemic heart disease event

Permanently discontinue enzalutamide

Other ≥G3 toxicity or intolerable side effect

Interrupt enzalutamide dosing for 1 week or until symptoms resolve to ≤G2, then resume at the same or a reduced dose (120 mg or 80 mg) if warranted

Strong CYP2C8 inhibitor is required

Reduce the enzalutamide dosage to 80 mg by mouth once daily

Strong CYP2C8 inhibitor is discontinued

Resume the enzalutamide dosage that was used prior to initiation of the strong CYP2C8 inhibitor

Strong CYP3A4 inducer is required

Increase the enzalutamide dosage from 160 mg to 240 mg by mouth once daily

Strong CYP3A4 inducer is discontinued

Resume the enzalutamide dosage that was used prior to initiation of the strong CYP3A4 inducer

Note: Advise patients of potential risk to a developing fetus. Advise women who are or may become pregnant not to handle enzalutamide. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of enzalutamide. Advise male patients to use a condom if having sex with a pregnant woman

Adverse Events (N = 1057)

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Adverse Events (N = 1057)

Enzalutamide (N = 871)

Placebo (N = 844)

Grade (%)^✫

Grade 1/2

Grade 3-5

Grade 1/2

Grade 3-5

Fatigue

Back pain

Constipation

Arthralgia

Decreased appetite

Hot flush

Diarrhea

Hypertension

Asthenia

Fall

Weight loss

Peripheral edema

Headache

Any cardiac adverse event^✫

Acute renal failure^✫

Atrial fibrillation^✫

Ischemic or hemorrhagic cerebrovascular event^✫

Elevated ALT level^✫

Acute coronary syndrome^✫

Seizure^✫

^✫Denotes those events of special interest

Note: Toxicities are included in the table if all-grade events occurred in ≥10% of patients and were ≥2 percentage points or higher than in the placebo group, or they were of special interest

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Chapter 32: Prostate Cancer

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INTRODUCTION

Expert Opinion

REGIMEN: ABIRATERONE ACETATE METASTATIC CASTRATION–RESISTANT PROSTATE CANCER—NO PRIOR CHEMOTHERAPY

REGIMEN: DOCETAXEL + PREDNISONE

REGIMEN: MITOXANTRONE + PREDNISONE (M + P)

ADVANCED DISEASE REGIMEN: ABIRATERONE ACETATE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER—PRIOR CHEMOTHERAPY

ADVANCED DISEASE REGIMEN: ENZALUTAMIDE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER—PRIOR CHEMOTHERAPY

ADVANCED DISEASE REGIMEN: CABAZITAXEL + PREDNISONE

ADVANCED DISEASE REGIMEN: KETOCONAZOLE + HYDROCORTISONE

ADVANCED DISEASE REGIMEN: RADIUM-223 METASTATIC CASTRATION-RESISTANT PROSTATE CANCER WITH BONE METASTASES

REGIMENS: HORMONAL AGENTS

IMMUNOTHERAPY REGIMEN: SIPULEUCEL-T

PROSTATE CANCER REGIMEN: ENZALUTAMIDE (BEFORE CHEMOTHERAPY)

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