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Predicting response to platinum chemotherapy in metastatic castration-resistant prostate cancer (mCRPC) using a genomic signature for "BRCAness": A phase II clinical trial of satraplatin in men with mCRPC who have progressed on docetaxel.

TPS191 Background: The BRCA genes preserve genomic integrity during double stranded DNA breaks via homologous recombination. Patients with germline BRCA mutations must utilize alternative repair pathways that are more error prone. Pre-clinical and early clinical studies have demonstrated that BRCA deficient tumors are particularly sensitive to platinum chemotherapy as they are unable to repair the DNA injury induced by platinum compounds, leading to cell death. Germline BRCA mutations are rare in solid cancers. However, 25% of patients with sporadic cancers acquire genetic changes in the BRCA genes conferring a phenotype similar to patients with germline mutations. Platinum compounds may have a greater role in these patients with sporadic cancers and "BRCAness." Satraplatin, is a fourth generation oral platinum active in cisplatin resistant tumors and associated with an increase in progression free survival in men with metastatic castration resistant prostate cancer. No study has evaluated the clinico-pathologic correlates of "BRCAness" in prostate cancer or utilized a genomic approach to pre-identify patients that would benefit from platinum chemotherapy.


METHODS
We have initiated a phase II clinical trial of satraplatin in men with metastatic CRPC who have progressed on docetaxel therapy. All men ≥ age 18 with radiographic evidence of metastatic disease amenable to image-guided biopsy will be eligible for trial participation. All patients will undergo a pre-study biopsy of a metastatic lesion and receive Satraplatin 80 mg/m2 orally on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily. We are concurrently developing a prostate cancer genetic signature for BRCAness derived from genomic profiles of BRCA1/2 breast cancers and standard estrogen-receptor (+) breast cancers. This signature will be applied to a large dataset of primary localized prostate cancers and later validated in an independent dataset of trial participants. We will be evaluating the efficacy of satraplatin in relationship to the BRCAness signature status. One of thirty patients has been enrolled.