Discussion
tumor, NEPC, neuroendocrine prostate cancer, mCRPC, prostate cancer
DISEASE PROGRESSION, TUMOR, BLOOD, PROSTATE CANCER, TUMORIGENESIS
The natural history of prostate cancer can be long, yet repeat biopsies are uncommon. Blood–based biomarkers create an opportunity for dynamic reassessment and therapy selection. This has become increasingly relevant as more treatments and combinations have become available for castration–resistant prostate cancer (mCRPC). This study evaluated a whole blood 6–gene RNA transcript–based signature and serum tissue inhibitor of metalloproteinase-1 (TIMP-1) levels as biomarkers for response to the oral platinum analog satraplatin (Demographics.The 6–gene RNA score was previously validated to have prognostic significance in mCRPC. However, no relationship was observed between changes to the score and response to satraplatin. The biological processes measured by the 6–gene score may be distinct from those that determine response to satraplatin. A prognostic score may be more suited to identify patients who need treatment intensification rather than predicting benefits from a specific agent.Tissue inhibitor of metalloproteinase-1 (TIMP-1) plays contradictory roles in tumorigenesis, opposing tumor invasion yet promoting cell growth and angiogenesis. Our data suggest that serum TIMP-1 levels may have some association with response to platinum therapy, as responders experienced an overall decrease in TIMP-1 levels, whereas non-responders had an overall increase. This is in line with observations that TIMP-1 levels are associated with neuroendocrine prostate cancer (NEPC), which is in turn associated with platinum sensitivity. Further evaluation is needed to evaluate the utility of trending TIMP-1 as a marker in NEPC.Due to the withdrawal of support, this study of satraplatin did not meet the originally planned enrollment goal of 30 patients, which limits the analysis. The primary endpoint of PSA response rate in the evaluable cohort of patients in this study is comparable to the experience with satraplatin in the phase III SPARC trial. As expected, responders to satraplatin had a clear advantage in time to disease progression (206 vs. 35 days, HR 0.26, 95% CI, 0.02-0.24, In the time since the inception of this study, many new treatment options have become available for patients with mCRPC, and platinum chemotherapy has largely been limited to the treatment of NEPC. This study highlights a few issues which remain relevant: (1) platinum chemotherapy has activity in mCRPC but a biomarker for platinum sensitivity is needed, (2) the need for a platinum sensitivity biomarker overlaps with the need for a consensus clinical or molecular definition of NEPC, and (3) liquid biopsies permit dynamic molecular reassessment and could enable optimal treatment sequencing in mCRPC.