Clinically Localized Disease at Presentation
As a result of widespread screening of men by PSA and DRE, the majority of patients are seen with clinically localized disease at diagnosis. Unfortunately, it is not always obvious how to match the individual patient with the most appropriate management. In an abstract sense, patients with clinically localized prostate cancer fall into one of four theoretical categories:
Those not destined to have any clinical manifestations of their disease. These patients are actually harmed by any intervention, including further surveillance.
Those destined to have a clinical manifestation of cancer but will not to die of it. These patients might benefit from definitive therapy (such as prostatectomy or radiation) but would likely benefit equally from less-morbid intervention (eg, minimally invasive surgery).
Those destined to have life-threatening disease for whom definitive therapy will be curative. Patients who can be cured, or for whom there will be a substantial alteration of the natural history of their disease, constitute the group that will unequivocally benefit from definitive local therapy.
Those destined to have life-threatening disease for whom the opportunity to cure by means of local therapy either never existed or passed. For these patients, however, control of the primary could still be an important component of an overall treatment strategy that considers the probability of local versus distant progression, comorbidity, and other factors.
The common practice of urologists and radiation therapists is to assume that nearly every patient falls into the third category, and thus they recommend definitive therapy for the vast majority of newly diagnosed cases of localized prostate cancer. Unfortunately, available evidence suggests that less than half of patients are in category 3, so it is not surprising that understanding the role of definitive therapy in eliminating prostate cancer morbidity and mortality has been both difficult and controversial. In fact, these issues underscore the fact that overtreatment of “clinically insignificant” prostate cancers certainly occurs. The significant cost and morbidity associated with local treatment also adds to the difficulty of managing these patients (whether the patient ultimately benefited from the therapy or not).
In patients with newly diagnosed localized disease, current prognostic and predictive models rely on data derived from large prostatectomy series conducted at major academic centers. For example, investigators at Johns Hopkins initially published a predictive model relating the rate of finding disease that is not confined to the prostate (by assessing the surgical specimen) as a function of three readily available preoperative clinical parameters: PSA, Gleason score from the core biopsy, and the clinical stage based on DRE (43,44). The correlation of these features with pathologically organ-confined disease, summarized in the famous “Partin tables,” provided sobering evidence that commonly encountered subsets of patients had a surprisingly high risk of disease that was not confined to the prostate. Of course, not all patients with pathologically organ-confined disease relapse, and not all patients with pathologically organ-confined cancers are cured. Thus, the importance of this particular surrogate outcome was and remains uncertain. Nevertheless, the effect of the Partin tables on clinical practice has been profound. They have driven the application of prostatectomy to patients with smaller and smaller volumes of cancer. It is clear that although more patients are remaining free of disease after prostatectomy, this comes paradoxically at the cost of operating on many patients who may not have needed surgery or not operating on many patients who would have benefited from good local control even if the surgery were not curative.
Additional models have been developed to predict outcomes following radical prostatectomy or radiation therapy. Based on the work of D’Amico, a combination of pretherapy PSA, Gleason score, and clinical stage can be used to stratify patients into low (T1-T2a and Gleason score 2-6 and PSA <10 ng/mL); intermediate (T2b-T2c or Gleason score 7 or PSA 10-20 ng/mL); high (T3a or Gleason score 8-10 or PSA >20 ng/mL); and locally advanced (T3b-T4) groups that predict risk for both biochemical recurrence and survival following definitive local therapy (radical prostatectomy or radiation) (45). Similarly, Kattan et al developed postoperative nomograms for predicting prostate cancer recurrence after radical prostatectomy (46). These tools not only help guide recommendations for individual patients, but also help stratify patients for clinical trials. For example, low-risk patients can be directed toward “active surveillance” trials, while high-risk patients can be direct toward adjuvant/neoadjuvant trials. The rationale for the use of predictive nomograms is outlined in Table 37-2.
Table 37-2Rationale for Use of Predictive Nomograms ||Download (.pdf) Table 37-2 Rationale for Use of Predictive Nomograms
Gleason grade, clinical stage, and initial PSA are predictive of surgical stage, risk of subsequent relapse, and risk of cancer-specific mortality.
Improving the ability to predict outcome will inform both physicians and patients about the risk/benefits of local therapy.
Fewer patients will undergo unnecessary or futile surgery.
Despite the efforts detailed previously, tumors with identical morphology and clinicopathologic characteristics often display biologic heterogeneity (ie, some “low-risk” tumors rapidly progress, while some “high-risk” tumors are relatively indolent). Thus, more refined models are needed. Recent efforts have sought to incorporate genetic tests to enhance current clinicopathologic risk stratification for patients newly diagnosed with localized prostate cancer. For example, PROLARIS (Myriad Genetics, Inc.) directly measures expression of 46 different genes in formalin-fixed paraffin-embedded tissue obtained by biopsy or prostatectomy (47,48,49), including 31 cell cycle progression (CCP) genes and 15 housekeeper genes that correlate with proliferation of prostate cancer. Low expression is associated with a low risk of disease progression, whereas high expression is more indicative of higher risk of disease progression, suggesting either close monitoring or additional therapy for the latter group of patients.
Other investigational approaches to improve risk stratification include assessing suspicious nodes or small-volume extracapsular extension by MRI or positron emission tomography, staging biopsies of seminal vesicles and extraprostatic tissue, and incorporation of molecular signatures. Within our group, a significant effort is under way to relate the expression of genes that may affect apoptotic threshold, invasion, angiogenesis, and AR signaling to biologic potential and ultimately clinical outcome of localized tumors. These data suggest that both loss of tumor suppressor pathways (eg, p53) and gain of oncogene/antiapoptotic pathways (eg, Bcl-2) contributes to prostate cancer progression. In addition to these and other “epithelial” events, the importance of the host-epithelial interaction in prostate cancer progression has been supported by evidence that pathways involved in paracrine regulation of normal stromal-epithelial interactions have also been implicated in prostate cancer progression (50,51,52).
Localized Low-Stage Prostate Cancer
In patients with localized low-stage disease (generally including low- and intermediate-risk groups based on the D’Amico risk stratification groups), the options offered include active surveillance, surgery, radiation, or presurgical clinical trials. Educating the patient about his treatment options is critical to make the best decision for each individual. Patients who are undecided or request more information about treatments and side effects are seen in our multidisciplinary clinic.
Critical evaluation of the relative merits of different therapies for localized low-stage prostate cancer is difficult. This is because patients in this category have a greater than 80% chance of 10-year progression-free survival following local therapy (53,54,55). Prostate cancer has a long natural history, and 10-year data for patients with low-risk prostate cancer remain immature with respect to cause-specific and disease-free survival. The contribution of delayed hormonal therapy and the appreciation that not all patients with a delayed PSA recurrence after local therapy are threatened by their disease have made comparisons between different treatment modalities difficult. As a consequence, the modification of older therapies or the application of new ones (such as brachytherapy, cryoablation, or proton beam therapy) is often judged by their complication profile and the rate of PSA-free survival with a relatively short follow-up. While seemingly logical, interpreting potential benefit from “new and improved” therapies is challenged by the impact of “stage migration” on outcomes. Stage migration refers to the fact that, as a consequence of awareness and PSA screening, younger patients with lower-stage cancer are diagnosed with increasing frequency. This trend of earlier therapy in younger patients with earlier-stage disease likely has an effect on the analysis of therapy efficacy and morbidity for low-stage cancer. Therefore, the practice of deriving conclusions from the comparison of nonrandomized study groups in low-stage prostate cancer is a dubious exercise.
In fact, in localized, low-stage prostate cancer, the principal therapeutic dilemma is whether to intervene at all. Increasingly, many investigators are recognizing that not all patients diagnosed with prostate cancer by histologic criteria have a disease that has lethal potential (56). Hence, many clinicians have explored a strategy of observation followed by delayed therapy if required. This strategy has historically been called “watchful waiting,” but in recent years we have adopted the term active surveillance. This is because the definition of watchful waiting is ambiguous and includes the practice of not following or evaluating patients after diagnosis until they present with a prostate cancer–associated symptom(s). In contrast, active surveillance implies regular follow-ups with PSA evaluation, DRE, and repeat biopsies as indicated to inform the need for local therapy. Active surveillance acknowledges the reality that many patients with prostate cancer survive despite diagnosis and therapy, as opposed to benefiting directly from the intervention. At MD Anderson, the rationale for offering active surveillance is the idea that carefully monitored patients will require therapy with curative intent only if accompanied by objective evidence that their cancer has become life threatening. In this way, patients with truly indolent disease can be spared the morbidities of local therapy, while patients who show progression over time to potentially lethal disease will preserve the opportunity for curative therapy.
Active Surveillance With Deferred Treatment
Two categories of patients with low-stage disease are generally considered for active surveillance: (1) men who have a higher probability of dying from a comorbid illness (such as coronary artery disease) than from prostate cancer and (2) men whose cancer poses some risk for lethality but choose active surveillance because of concerns about consequences of therapy (eg, impotence or incontinence). The rationale for active surveillance is outlined in Table 37-3.
Table 37-3Rationale for Active Surveillance ||Download (.pdf) Table 37-3 Rationale for Active Surveillance
A significant portion of newly diagnosed patients will not develop clinical progression.
Complications of local therapy exceed benefits in some patients.
Close monitoring of selected patients with serial PSA measurements may avoid or delay initiation of potentially morbid or unnecessary therapy.
There are two central challenges of the active surveillance strategy. The first is that we do not yet have a validated method to anticipate progression of the disease to avoid “closing the window” on curative therapy. The second is that we lack methods to ensure reliable selection of all patients in whom the disease will be unlikely to spread while excluding all patients who will have lethal progression of the disease despite its initial morphologic appearance as low stage. Thus, this strategy, while supported by compelling logic, must be regarded as unproven. This is particularly true for those patients with a life expectancy of 15 years or more. As a patient’s life span shortens due to comorbid conditions, the unproven nature of this strategy has less predicted impact on outcome. Thus, outside a clinical trial, active surveillance in our practice is routinely reserved for patients with low-stage disease and an expected survival of less than 10 years due to comorbidities.
Active surveillance for category 1 patients is not codified, and follow-up strategies (such as annual PSA checks) are designed by mutual agreement between the physician and patient. Select elderly patients whose cancer diagnosis was precipitated by an ill-advised PSA screening test may choose no further follow-up. In contrast, active surveillance for category 2 patients involves close observation with quarterly PSA checks and annual prostate biopsies. Often, these patients elect to undergo local therapy as the physical and emotional burden of close observation becomes more obvious. Despite the intensity of follow-up, the ability to anticipate progression of disease based on true biologic evidence as opposed to apparent progression caused by the randomness of the biopsies remains a major problem. These problems will be clarified with prospective studies accruing at several institutions.
Treatment of Low-Stage Disease With Available Therapy
Although there is much debate about the relative merits of radiation therapy and surgery for patients with localized low-stage prostate cancer, the inescapable conclusion is that both treatment groups have excellent survival, and the principal issues influencing choice are related to therapy-associated morbidity. Interestingly, competition between radiation therapy and surgery has resulted in the reduction of morbidity to both therapies. The morbidity of radiation therapy—while retaining its effectiveness—has been greatly reduced, as has morbidity related to improvements in surgical techniques. Thus, for low-stage prostate cancer, the principal therapeutic recommendation is to treat those patients who have a greater than 15-year expected life expectancy. The primary recommendation is surgery or radiation therapy, with a bias toward surgery for those patients with an expected longevity of more than 20 years and a bias toward radiation therapy for those patients with an expected longevity of 15 years or less (Table 37-4).
Table 37-4Rationale for Selection of Local Treatment Modality ||Download (.pdf) Table 37-4 Rationale for Selection of Local Treatment Modality
There are no clinical trials showing a therapeutic advantage of surgery over radiation therapy for localized disease.
Either approach is associated with some risk of significant morbidity (initial impotence rates are higher with surgery).
There is a reduction in impotence rates over time with radiation.
Surgery provides better assessment of risk for future relapse by allowing molecular-pathologic analysis of the radical prostatectomy specimen.
Radiation is ideally suited for patients who are physically unfit for surgery or those who have disease extending beyond the bounds of traditional surgical fields.
Surgery improves symptom-free and overall survival in patients with localized disease.
Presurgical Trials for Low-Stage Disease
Presurgical trials facilitate the development of novel therapies and treatment strategies in prostate cancer by providing proof of “target engagement” by the drug(s) and modulation of the tumor phenotype in a therapeutically favorable manner (57). The principal goal of a preoperative clinical trial is to identify short-term molecular and pathologic tissue surrogates that establish target engagement and modulation of key signaling pathways by the drug(s). Because surgery is performed before cytoreduction or significant changes in the tumor phenotype are expected (as opposed to neoadjuvant trials), preoperative trials provide only limited inferences about the therapeutic potential of the drug(s) being tested. However, data from preoperative trials help identify the most promising therapeutic candidates worthy of further study. Preoperative studies of low-stage prostate cancer seek to identify molecular markers that characterize response to therapy and predict tumor biology.
High-Risk and Locally Advanced Prostate Cancer
As a general principle of oncology, high-risk and locally advanced tumors (based on the D’Amico risk stratification groups) are best treated with a combination of systemic therapy and aggressive local therapy. This strategy addresses occult disseminated disease while preventing local complications of the primary tumor. Despite the widely recognized poor outcomes for patients with seminal vesicle or regional node involvement, the application of optimum local control with systemic therapy has only recently become accepted (58).
Current multimodal therapies include radiation plus hormones and neoadjuvant therapy plus surgery. It is now well established that the addition of hormones to radiation therapy is superior to radiation therapy or hormones alone for patients with high-risk and locally advanced tumors (59). The duration and sequence of the combination are important in maximizing therapy benefit from the combination. Several lines of evidence suggest that initiating the androgen ablation 2 months prior to the radiation therapy is more effective than combined therapy from the outset or sequential therapy with radiation followed by androgen ablation. The available data demonstrate an increase in survival with a 3-year period of androgen ablation. However, the optimal duration of androgen ablation in the context of locally advanced prostate cancer treated with radiation remains an area of investigation.
It also appears that improved local control represents another strategy to improve overall survival (OS) in patients with T3N0M0 (TNM, tumor-node-metastasis) tumors. Randomized controlled trials have demonstrated that adjuvant radiation therapy following radical prostatectomy for T3N0M0 tumors significantly reduces the risk of metastases and improves OS (60). These data support the hypothesis that untreated residual disease at the primary site can act as a source for metastatic progression.
Neoadjuvant Trials in High-Risk and Locally Advanced Prostate Cancer
At MD Anderson, we recognize two different categories of patients with high-risk or locally advanced disease: (1) those we believe can be effectively treated with hormones and radiation therapy and (2) those we believe will not be effectively treated with this approach because of the extent of their disease, adverse histologic features of the tumor, or the relative youth and expected long survival of the patient. Patients in the second category are candidates for a novel preoperative therapy given prior to prostatectomy. The rationale for neoadjuvant therapy in this setting is based on progress made in other cancer types and is described as follows: (1) In high-risk and locally advanced disease, the posttherapy pathology specimen will inform both prognosis and future treatment decisions, and (2) controlling the primary tumor is an essential part of an integrated strategy for patients with high-risk and locally advanced disease (although this strategy is not always curative) (61). We are using neoadjuvant trial designs with increasing frequency to develop novel agents (eg, angiogenesis inhibitors) in prostate cancer. Analysis of the prostatectomy specimen permits detailed analysis of molecular (eg, apoptosis) and pathologic surrogates for therapy benefit (eg, achievement of Pathologic 0 stage-P0). We believe the preoperative model will significantly enhance our ability to identify the most promising agents worthy of development in a time-efficient manner.
A promising combined modality approach has recently been reported utilizing maximal androgen blockade of both endocrine (using luteinizing hormone-releasing hormone agonists) and paracrine/autocrine/intracrine (using abiraterone, a CYP17 inhibitor) testosterone sources. Two recent phase 2 studies demonstrated that combination leuprolide/abiraterone was clinically superior to leuprolide alone with respect to PSA responses and cytoreduction (62,63). A subset of patients in both trials achieved P0 (or near P0) in the surgical specimen, a relatively common phenomenon in neoadjuvant trials of other epithelial cancers (eg, breast and bladder) but essentially unprecedented in prostate cancer.
Castration-Resistant Locally Advanced Prostate Cancer
Castration-resistant prostate cancer (CRPC) is an “umbrella” term that encompasses a spectrum of disease states ranging from rising PSA alone to rising PSA associated with osseous or soft tissue metastases (1). Furthermore, patients receiving combined androgen blockade are typically screened for an antiandrogen withdrawal response before being considered castration resistant. Patients with CRPC and PSA-only recurrence are discussed in the next section.
For patients with castration-resistant locally advanced prostate cancer, clinical progression presents significant clinical symptoms (pain, hematuria, bladder outlet and bowel obstruction), but optimal management remains a difficult therapeutic problem. The critical decision is whether to offer consolidative therapy. For patients without metastatic disease, we offer neoadjuvant chemotherapy followed by surgery for consolidation. If not used as primary therapy, salvage radiation therapy is another rational strategy, particularly for patients who are not candidates for salvage surgery.
For patients with both castration-resistant locally advanced and metastatic disease, these approaches are more controversial. Nonetheless, we recognize that these patients experience significant morbidity from local tumor progression that is comparable to patients without metastases. Thus, for select candidates, we still offer consolidative therapy. As an example, consider the case of a patient who presented with metastatic prostate cancer at diagnosis and was successfully treated with androgen ablation for 10 years. He then developed castration-resistant progression and presented with invasion of his primary tumor into the bladder (Fig. 37-3). To relieve painful voiding symptoms attributed to the bladder invasion, induction chemotherapy followed by salvage cystoprostatectomy was performed. At 3 years follow-up, the patient continued to have evidence of active metastases but was free of cancer-associated local symptoms. While this patient benefited longer than most, striking relief of intractable symptoms is common using this approach. The clinical rationale to apply chemotherapy followed by salvage surgery is summarized in Table 37-5.
Table 37-5Rationale for Salvage Surgery ||Download (.pdf) Table 37-5 Rationale for Salvage Surgery
Patients can avoid significant morbidity associated with local progression.
Improved local control may contribute to longer overall survival.
Patients who develop a delayed local relapse after treatment with primary radiation therapy may still have surgically curable disease.
Recurrent prostate cancer invading the base of the bladder.
Rising Prostate-Specific Antigen After Definitive Local Therapy
The utility of PSA measurements is greatest in monitoring cancer progression and effects of therapy in patients with radiographic evidence of disease. In contrast, the significance of PSA in patients without detectable disease is less clear. Although available evidence suggests that patients with a measurable PSA following prostatectomy will eventually develop a recurrence given sufficient time, these recurrences are not uniformly fatal. Furthermore, in patients treated with radiation therapy, interpretation of PSA posttherapy is very different compared to patients treated with surgery.
Significance of Prostate-Specific Antigen Following Prostatectomy
The serum PSA concentration should be undetectable using standard commercial assays within 6 weeks of prostatectomy. Persistent PSA following surgery usually indicates persistent cancer secondary to inadequate surgery, persistent cancer despite adequate surgery, or the presence of occult metastases. The experience from Johns Hopkins suggests that, given sufficient time, patients with early PSA recurrence (≤2 years) or short PSA doubling time (<10 months) will develop metastatic disease within 15 years of surgery (64,65,66). In contrast, patients with late PSA recurrence or a longer PSA doubling time are more likely to have a recurrence confined to the prostatic fossa. Patients who have a striking discordance between the predicted behavior of the cancer (eg, low stage) and early elevations of postoperative serum PSA may have had inadequate surgery and are considered for adjuvant radiation therapy. In patients who undergo nerve-sparing prostatectomy, consideration must also be given to the possibility that normal prostate gland left behind at surgery is producing PSA.
Significance of Prostate-Specific Antigen Following Radiation Therapy
In contrast to surgery, serum PSA concentrations are not expected to become undetectable following curative therapy. In addition, the phenomenon of a PSA “bounce” is well described following radiation of the primary tumor (67). The PSA bounce is a modest, self-limited rise in PSA concentration without evidence of cancer progression. It typically occurs within the first 18 months following completion of radiation and can last for as long as 3 months before reaching a plateau and then declining. The central clinical dilemma with PSA bounces is that their presence can only be determined with confidence in retrospect. Thus, clinicians need to be aware of this phenomenon and show restraint in introducing therapy to patients displaying delayed PSA elevation after radiation without evidence for metastases.
Management of the Patient With Prostate-Specific Antigen–Only Recurrence
The scenario of the patient with prostate-specific antigen–only recurrence poses a therapeutic dilemma for physicians and considerable anxiety for patients. As experience with this disease state matures, it is becoming clear that PSA-only recurrences do not uniformly portend morbidity/mortality from the disease. Our general approach is to offer hormone ablative therapy (commonly using an intermittent strategy) during the androgen-dependent phase of the disease (68). Notably, we never use chemotherapy for PSA-only recurrences that occur in the setting of CRPC. Instead, we advocate placing these patients on clinical trials testing novel compounds.
Currently, we are conducting a clinical trial at our institution (NCT01786265) that is testing whether more potent inhibition of androgen synthesis will help. The goal of this clinical research study is to determine whether inhibition of paracrine/autocrine/intracrine androgens (using abiraterone) in addition to endocrine androgens (using leuprolide) will improve efficacy in this patient group. A key data point will be PSA-free survival, defined as duration of time “off” therapy with an undetectable PSA and return of testosterone levels.
Metastatic Androgen-Dependent Disease
For patients with visible disease in the bone or lymph nodes, the standard approach is continuous androgen ablation. The clinical rationale for the use of androgen ablation is summarized in Table 37-6. For patients with de novo metastatic disease and primary tumors in place, we are currently conducting a clinical trial (NCT01751438) to test best systemic therapy versus best systemic therapy plus definitive treatment (radiation or surgery) of the prostate. The goal of this clinical research study is to learn if control of the primary tumor improves the clinical outcome in patients with metastatic disease. The safety of this combined modality treatment combination will also be studied.
Table 37-6Clinical Rationale for Androgen Ablation ||Download (.pdf) Table 37-6 Clinical Rationale for Androgen Ablation
Androgen ablation enhances local therapy:
Concurrent androgen ablation and radiation therapy increase survival in selected patients.
Early use of androgen ablation in patients noted to be node positive following radical prostatectomy increases overall survival.
Timing of androgen ablation:
The decision to introduce androgen ablation among patients with a rising PSA following local therapy should be based on assessment of risk for recurrence and cancer-associated mortality.
Androgen ablation therapy reduces the duration of time patients experience symptomatic progression.
Symptoms are reliably relieved and should be initiated in the presence of symptomatic progression.
Types of androgen ablation:
Surgical castration and LHRH agonists or antagonists are considered to be equally effective.
Combined androgen ablation is not convincingly superior to serial use of an LHRH agonist followed by an antiandrogen on progression. However, antiandrogen therapy should precede the use of an LHRH agonist in the setting of threatening disease to avoid a “surge.”
Secondary hormonal therapy:
Management of complications associated with androgen ablation:
Patients on sustained androgen ablation should be monitored for bone complications and considered for bisphosphonate therapy to reduce the risk of osteopenia.
Supplementation with calcium (500 mg) and vitamin D (400 IU) is recommended.
Antidepressants should be considered for androgen ablation–associated depression.
The role of cytotoxic chemotherapy in patients with androgen-dependent disease remains controversial. Most recently, data from the CHAARTED trial comparing “up-front” chemotherapy plus androgen deprivation therapy (ADT) to ADT alone in men with metastatic prostate cancer was reported. The results showed that, in men with high-volume disease (defined as visceral metastasis and/or ≥4 bone metastases), median OS was 49.2 months with docetaxel plus ADT compared with 32.2 months with ADT, a difference of 17 months (69). Although the final manuscript is pending publication at this point, this study suggests that patients with high-volume, androgen-dependent disease may benefit from up-front docetaxel.
However, in contrast to those data, other large phase 3 studies of similar design have been negative (70,71). The GETUG-AFU 15 trial recently reported no differences in OS between patients with noncastrate metastatic disease receiving ADT plus docetaxel versus ADT alone (median OS was 58.9 months in the group given ADT plus docetaxel and 54.2 months in the group given ADT) (71). It is likely that differences in patient populations (eg, volume of disease at baseline) and treatments postprogression explain the disparate results between these trials. At our institution, while our clinical experience strongly supports the notion that some patients with metastatic disease will benefit from early application of cytotoxic chemotherapy (eg, patients with small cell/anaplastic features), we offer it on a case-by-case basis rather than routinely.
Second-Line Hormonal Therapies
During castrate-resistant progression, there is a gradual “switch” in sources of androgens that sustain tumor growth from endocrine to intratumoral (paracrine/autocrine/intracrine). Second-line hormonal therapies that block these alternative sources have long been of interest as cancer therapeutics. For example, considerable advances have been made in developing small molecule inhibitors that block CYP17, a key enzyme involved in androgen biosynthesis expressed in testes, adrenal glands, and tumor tissues (72). Ketoconazole is an antifungal agent with weak and nonspecific CYP17 inhibitory properties that has been available for decades. While ketoconazole is active in prostate cancer, its application has been limited due to extremely poor tolerance. In contrast, several new agents, including abiraterone, have proven more successful. Abiraterone is a potent irreversible inhibitor of CYP17, and two large randomized phase 3 studies have demonstrated clinical benefit in both chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer (mCRPC) (73,74).
Enzalutamide (Xtandi; Medivation/Astellas) is a small molecule that directly binds the AR to competitively inhibit endogenous androgen binding and antagonize AR function. It has a higher affinity for the AR than first-generation nonsteroidal antiandrogens (eg, bicalutamide). Randomized phase 3 studies have demonstrated that enzalutamide is clinically beneficial in both chemotherapy-naïve and docetaxel-treated patients with mCRPC (75). Because enzaluatmide can potentially address molecular resistance mechanisms to abiraterone monotherapy and vice versa, studies of combination abiraterone and enzalutmide are also under way. More specifically, resistance to abiraterone is associated with increased nuclear AR copy number (theoretically blocked with enzalutamide), and resistance to enzalutamide is associated with increased microenvironment testosterone levels (theoretically blocked with abiraterone) (76,77). Preliminary analysis suggested that a higher percentage of patients experience favorable PSA response profiles than seen with either agent alone, and the combination appears to be well tolerated (78).
Although abiraterone and enzalutamide represent breakthroughs in the treatment of mCRPC, approximately 20% to 40% of patients have no response to these agents (primary refractory). Furthermore, among patients who initially have a response to enzalutamide or abiraterone, virtually all eventually acquire secondary resistance. For example, the emergence of mutations (such as a single F876L amino acid substitution) in the AR can confer resistance to enzalutamide. Recently, Antonarakis et al reported detection of AR-V7 in circulating tumor cells from patients with CRPC may be associated with resistance to enzalutamide and abiraterone (79).
Prostate cancer has now entered the realm of the other adult common solid tumors in that chemotherapy is routinely applied to patients with castration-resistant locally advanced or metastatic disease. For more than a decade, patients have been treated with docetaxel-based regimens. However, while these therapies improve quality of life, prolongation in survival is modest. Faced with these challenges, the approach at MD Anderson has been to delay cytotoxic therapy until second-line hormonal (or experimental options) have been explored. Of course, patients with rapidly progressive disease causing (or expecting to cause) symptoms are offered chemotherapy sooner rather than later, particularly when additional hormonal manipulations are predicted to fail (eg, in patients with small cell/anaplastic tumors). The rationale for the use of chemotherapy is outlined in Table 37-7.
Table 37-7Rationale for the Use of Chemotherapy ||Download (.pdf) Table 37-7 Rationale for the Use of Chemotherapy
Chemotherapy palliates or prevents symptoms associated with progression of disease.
Docetaxel-based regimens result in modest improvements in survival in patients with metastatic castration-resistant cancer.
Other active agents in prostate cancer (eg, mitoxantrone and prednisone) can be used as second-line therapy.
Given the limitations of docetaxel-based chemotherapy, there has been a global research initiative to improve on it, principally by combining docetaxel with other agents. However, these efforts have met with little success. For example, antiangiogenic drugs such as sunitinib and avastin did not improve OS compared with placebo in docetaxel-refractory mCRPC (80,81). Similarly, bone microenviroment targeting agents such as zibotentan, atrasentan, and dasatinib were each tested in phase III trials and all failed to improve on standard docetaxel (82,83,84). Interestingly, each of these agents showed promise in phase II studies, and some (eg, avastin and sunitinib) did result in improvements in median progression-free survival. These results suggest that a subset of patients did benefit and that moving forward, clinical trial designs that incorporate predictive biomarkers to enrich for patients most likely to respond will be necessary to develop novel treatment strategies.
Optimizing Therapy Benefit Using Different Cytotoxic Agents in Metastatic Castration-Resistant Prostate Cancer
The concept that patients can respond to another taxane after progressing on docetaxel is important. The recent approval of cabazitaxel by the Food and Drug Administration (FDA), based on the results of the phase III TROPIC study, provided further validation of this concept (85). Cabazitaxel is a novel semisynthetic taxane developed specifically to overcome docetaxel resistance, and it is typically offered as second-line therapy for patients with mCRPC previously treated with docetaxel. This promising advance suggests that further study of cabazitaxel is warranted to explore its potential to overcome taxane resistance.
Beyond docetaxel and cabazitaxel, multiple chemotherapy regimens with modest activity are routinely applied in a sequential manner to patients in the salvage setting. Examples include CVD (cyclophosphamide, vincristine, and dexamethasone); KAVE (ketoconazole plus doxorubicin alternating with vinblastine plus estramustine); TEC (paclitaxel, estramustine, and carboplatin); and TEE (paclitaxel, estramustine, and etoposide). However, there is no standard chemotherapy in the salvage setting, and we do not have randomized comparisons testing whether the sequential application of therapy prolongs survival.
More recent studies have demonstrated clinical responses to platinum-based therapy in combination with taxanes (86,87,88). Ross et al tested the activity of docetaxel/carboplatin in patients that had progressed during or within 45 days after the completion of docetaxel (89). PSA declines of 50% or greater were noted in 18% of patients, and measurable responses occurred in 14% of patients. As patients in this study would not be anticipated to respond to “rechallenge” with docetaxel alone, these results support the hypothesis that carboplatin has the potential to overcome docetaxel resistance mechanisms.
We are presently conducting a randomized phase I/II study of cabazitaxel with or without carboplatin in patients with mCRPC (NCT01505868). Patients are stratified by prior docetaxel exposure, performance status, and presence of anaplastic features. Preliminary results suggest excellent safety and efficacy of the two-drug combination.
Bone-targeting radiopharmaceuticals are examples of stromal-targeting agents in prostate cancer. The merits of targeting the bone microenvironment have been established by the use of strontium 89 (pure β-emitter radiopharmaceutical) as a single agent or in combination with cytotoxic therapy (90) (Table 37-8). Emerging data support the view that targeting bone will prolong overall patient survival, even in those with advanced-stage disease. Samarium-153 conjugated to ethylene-diamine-tetra-methylenephosphonic acid is a β- and γ-emitter radiopharmaceutical. It was approved by the FDA in 1997 after the landmark study that showed palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam (91). However, marrow toxicity remains the principal side effect. The radioactive calcium mimetic radium-223 dichloride (Xofigo; Bayer), which specifically targets bone metastases (present in 80%–90% of patients with metastatic CRPC), is the newest treatment for mCRPC. A phase III, randomized, double-blind, placebo-controlled study (ALSYMPCA) investigated the use of radium-223 in men with CRPC and bone metastases; radium-223 showed improved OS in this patient population (92). This study led to its FDA approval for CRPC with bone metastases in 2013.
Table 37-8Rationale for Bone-Targeted Therapy ||Download (.pdf) Table 37-8 Rationale for Bone-Targeted Therapy
Osseous metastases are the preferred site of castration-resistant progression.
Osseous metastases significantly contribute to the morbidity and mortality of prostate cancer.
Bone-targeting radiopharmaceuticals prolong symptom-free survival in patients with castration-resistant progression and skeletal metastases.
Bisphosphonates were the first class of agents investigated for prevention of skeletal-related events (SREs) in patients with mCRPC. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma showed zoledronic acid reduced SREs in patients with prostate cancer with bone metastases (93). Currently, zoledronic acid is the only bisphosphonate approved to prevent SREs in patients with mCRPC.
Denosumab is a fully humanized monoclonal antibody that binds to the RANK-L, which results in inhibition of RANK-L–mediated bone resorption. In a phase III study, men with CRPC with bone metastases and no previous exposure to intravenous bisphosphonate compared denosumab with zoledronic acid for prevention of SREs (94). Denosumab was superior to zoledronic acid in delaying or preventing SREs, but there was no significant difference between treatments in survival or disease progression (94). It was approved by the FDA in 2010 for prevention of SREs in patients with bone metastases.
Historically, there has been long-standing interest in stimulating a patient’s immune system as a therapy strategy for prostate cancer. Despite enthusiasm for this paradigm, studies have consistently demonstrated no clinical benefit. Recently, several new strategies have emerged that reveal the potential of immunotherapy in treating prostate cancer. Randomized, placebo-controlled phase III trials demonstrated an OS benefit for men with CRPC treated with sipuleucel-T (95). GVAX, a cellular vaccine product that uses exogenous tumor cells that secrete granulocyte-macrophage colony-stimulating factor, has shown promising activity in phase II studies (96), although it failed to meet its primary end point of OS when compared with docetaxel in a phase III study (97,98). Ipilimumab is a humanized anti-CTLA-4 antibody; recent data from a phase III trial of a single dose of radiation treatment followed by ipilimumab or placebo in previously treated patients showed the primary end point (ie, OS) was not met (ipilimumab vs placebo, 11.2 vs 10.0 months, respectively; however, there was an improvement in progression-free survival and PSA responses) (99). Another phase III trial has completed enrolling patients with less-advanced, chemotherapy-naïve mCRPC. Further development of these agents (and others) could dramatically change the way we treat prostate cancer in the coming decade.