Carboplatin or Olaparib for BRcA deficient prostate cancer (COBRA)

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Abstract Advanced prostate cancer is a universally lethal disease and one for which no biomarkers have yet been found to inform therapeutic decision making. DNA repair deficiency in the homologous recombination pathway increases sensitivity of tumors to DNA damaging agents for patients with breast and ovarian cancers. Early data suggests that the DNA damaging agent carboplatin may be exceptionally effective in DNA repair deficient prostate cancer. This study would determine if the use of the DNA damaging agent carboplatin is more effective than docetaxel in homologous recombination deficient prostate cancers in the first line setting and compare responsiveness to the alternate drug at crossover. The proposed study is a randomized phase II study of first line carboplatin vs. docetaxel in men with metastatic, castration resistant prostate cancer containing BRCA1 or BRCA2 or PALB2 mutations after prior therapy with abiraterone and/or enzalutamide and for whom chemotherapy is considered appropriate. Patients will be treated with first line therapy until progression, intolerance or 10 cycles. At the time of progression, patients will cross over to the alternative regimen. The primary endpoint will be progression free survival with the first line therapy (PFS-1L) with secondary endpoints of progression free survival with second line therapy (PFS-2L) and PFS to both therapies combined as well as toxicity of each regimen. This study will provide critical information regarding efficacy and toxicity of carboplatin vs. the standard of care chemotherapy and whether use of DNA targeting agents initially will provide longer PFS than first line docetaxel. The importance of this study will be to establish the utility of BRCA and PALB2 as predictive biomarkers for carboplatin and to determine if carboplatin alone is an effective and safe therapy in men with resistant prostate cancer. The study would also establish whether carboplatin is appropriate to test in future studies against other agents targeting DNA repair pathway deficiency such as poly(ADP-ribose)polymerase inhibitors (PARPi). PARPi are very effective in early studies but are expensive and can be toxic. If this study demonstrates efficacy of carboplatin, randomized cost effectiveness studies vs. PARPi within the VA would be justified.