Using Surrogate Biomarkers to Predict Clinical Benefit in Men with Castration-Resistant Prostate Cancer: An Update and Review of the Literature

Abstract

Recurrent prostate cancer has a complex molecular etiology and a prolonged disease course. Although initially responsive to androgen ablation, many men eventually become castration resistant, develop skeletal metastases, and are palliatively treated with docetaxel-based chemotherapy, radiation therapy, bisphosphonates, and best supportive care. Given the modest success rates of the current standard of care, clinical trial enrollment is encouraged. Castration-resistant prostate cancer (CRPC) is a heterogeneous disease, both in clinical manifestations and outcomes, requiring an individualized approach to both patient care and trial design. Herein, we review surrogate markers of disease progression and treatment efficacy in advanced prostate cancer in light of recently published guidelines that have redefined eligibility, response criteria, and suitable endpoints in prostate cancer drug development. The guidelines have refined outcome measures to potentially better capture clinical benefit and the ability of novel targeted molecular and biologic agents to impact favorably on this disease. We consider prostatespecific antigen changes, circulating tumor cells, bone scan alterations, markers of bone metabolism (urinary N-telopeptide and bone-specific alkaline phosphatase), pain improvements, and progression-free survival. To illustrate the role and challenges of these potential biomarkers and endpoints in drug development, we discuss a class of novel molecularly targeted agents, the src kinase inhibitors. Given that there are currently no validated surrogate markers of overall survival for assessing early clinical benefit from systemic therapy in metastatic CRPC, incorporation of relevant biomarkers into all phases of clinical development is essential to accelerate drug development in this field. The Oncologist

Bone turnover markers in serum and urine as diagnostic, prognostic and monitoring biomarkers of bone metastasis

“…Most patients with bone metastases experience complications, the so-called skeletal-related events that summarize hypercalcemia, severe bone pain, pathological bone fractures, spinal cord compression, and surgery to bone because of bone instability. Thus, an early diagnosis and specific prediction of patients at risk of skeletal complications is of great interest to improve the clinical management of these patients not only in reducing these complications but also increasing overall survival by a bone-targeted therapy [3][4][5].…”

PSA-based treatment response criteria in castration-resistant prostate cancer: promises and limitations

“…4,5 However, the degree of surrogacy of this endpoint varied between these 2 studies and it is not considered as an endpoint for approval of cytotoxic agents by the regulatory agencies. 6 In this issue of CUAJ, Hanninen and colleagues 7 present data on another PSA-based endpoint, i.e., PSA half-life (PSAHL), obtained retrospectively from a chart review of 154 patients with metastatic CRPC treated with docetaxel in Alberta between 2000 and 2006. Using the PSAHL determined 84 days following initiation of docetaxel and a cutoff of 70 days, a strong association with survival is demonstrated: the median survival of patients with a PSAHL <70 days is 25 months compared to 15 months in patients with a slower rate of PSA decline (PSAHL ≥70 days).…”

“…Third, up to 20% of patients can experience PSA flares in the first weeks of docetaxel therapy despite subsequent response, which challenges the use of PSA-based criteria as an early marker of treatment benefit. 6 Finally, the interpretation of PSA data will be even more obscured with the increasing use of molecularly targeted agents, some of which result in dissociated antitumour/PSA effects, as is the case for sorafenib. 10 The authors acknowledge that the retrospective nature of the study is a major limitation.…”

Bone-targeted Novel Cytotoxic Polybisphosphonate Conjugate in Castration-resistant Prostate Cancer: A Multicenter Phase 1 Study

“…Even though some patients showed stabilization/drop in PSA, the data showed considerable variability. In general, there are several significant cautions to consider regarding interpretation of changes of PSA values over time, especially when evaluating new targeted cytotoxic therapies (28,29). The MTD dose (3 mg/kg) determined in this study, will be further investigated in a pending randomized double-blind dose-finding multicenter phase 2 study.…”