Response to olaparib or carboplatin in a real-world cohort of men with DNA damage repair (DDR) deficient metastatic castration-resistant prostate cancer (mCRPC).

Abstract

43 Background: PARP inhibitors (PARPi) and platinum chemotherapy cause synthetic lethality and result in clinical benefit in men with mCRPC whose tumors harbor deleterious alterations in DDR genes. BRCA2 is the strongest predictor, but data supports a role for BRCA1, ATM, and other genes. PARPi are more expensive than platinum chemotherapy; whether they are more effective is not known. We evaluated outcomes in men with DDR-deficient mCRPC treated with PARPi or platinum chemotherapy. Methods: We identified men treated at Dana-Farber Cancer Institute who received olaparib or carboplatin for mCRPC and underwent tumor mutation profiling. Progression-free survival (PFS) was determined using Prostate Cancer Working Group 3 guidelines. Pathogenic germline or somatic single-nucleotide variants, insertions/deletions, and copy number loss in BRCA2, BRCA1, and ATM, were identified. Log-rank test was utilized to compare differences in PFS. Results: We identified 27 men who received olaparib: 19/27 (70.4%) received prior taxane chemotherapy and 3/27 (11.1%) prior carboplatin; 16 had mono- or bi-allelic alterations in BRCA2 and 2 had alterations in BRCA1 or ATM. We identified 41 men treated with carboplatin: 39/41 (95.1%) received carboplatin in combination with a taxane; 36/41 (87.8%) received prior taxane chemotherapy and 7/41 (17.1%) prior PARPi; 16 had BRCA2 alterations and 5 had alterations in BRCA1 or ATM. Among men with BRCA2 alterations, there was no significant difference in PFS (HR 0.71, 95% CI 0.45-1.11; p = 0.13) between those treated with olaparib (4.9 months [m]) versus carboplatin (5.4 m). Similarly, no difference in PFS (HR 0.80, 95% CI 0.54-1.16; p = 0.24) was observed among men with BRCA2, BRCA1, or ATM alterations treated with olaparib (3.8 m) versus carboplatin (3.6 m). Conclusions: In a small real-world cohort of men with mCRPC harboring deleterious alterations in BRCA2, BRCA1, and ATM, there was no difference in PFS between those treated with olaparib versus carboplatin. These findings support further investigation into the comparative effectiveness and cost-effectiveness of PARPi and platinum chemotherapy in men with DDR-deficient mCRPC.