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Patients that develop recurrent metastatic prostate cancer have a poor prognosis. Although hormonal therapy in the form of medical or surgical castration can induce significant long-term remissions, development of castration-resistant disease, also termed castration-adapted, androgen-independent, or hormone-refractory prostate cancer (HRPC), is inevitable. Systemic therapy for metastatic prostate cancer is remarkable for the relatively few options that have been developed. Other than hormonal therapy, most treatments that have been approved for use have been for symptomatic benefit, such as mitoxantrone chemotherapy [1], the bisphosphonate zoledronic acid [2] and radioactive isotopes [3]. Despite multiple trials of cytotoxic chemotherapy in patients with metastatic HRPC, only docetaxel has been shown to improve overall survival [4, 5]. Part of the problem of a lack of therapeutic options is due to the prolonged natural history of prostate cancer and the patient population that it affects: generally older patients with concomitant medical problems and a higher risk of death from other causes [6]. This can make accrual to clinical trials more difficult [7] and create difficulties with detecting effects of a new therapy on overall survival.

Compounding the difficulties in the development of systemic therapy for prostate cancer is the lack of reliable intermediate endpoints in order to assess the activity of a new treatment, and in turn to judge and plan whether or not to proceed with large randomized comparative studies. In HRPC, objective disease progression may be lacking, and rising serum prostate-specific antigen (PSA) may be the only quantifiable measure of disease progression. Also, patients generally do not present with measurable tumour masses; when they do occur, they tend to be within lymph nodes, of small size and uncertain significance [8]. Bone is the predominant site of metastases in HRPC but determining whether a response or progression has occurred can be difficult. Post-therapy decreases in serum PSA are frequently used to assess activity; however, PSA ‘response’ has not been established as a surrogate for a clinical benefit [9]. Even defining when progression has occurred is problematic as it can be discordant between symptoms, measurable disease criteria, bone scan and PSA changes.

Over the past decade, our understanding of the molecular mechanisms of cancer progression has greatly expanded and a plethora of new targets based on these mechanisms have emerged. Novel therapeutics directed against these targets have closely followed; however, the development of these agents in prostate cancer has been a challenge for the reasons discussed above and the sheer volume of agents and drug combinations available for testing. This emphasizes the importance of clinical trial design and choice of appropriate endpoints when testing these agents in order to identify early those most promising to move forward, but also to not prematurely discard potentially useful treatments. This chapter will review the endpoints that have been utilized in recent clinical trials for men with prostate cancer ...

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