Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

Platinum-based chemotherapy is not standard of care for unselected or genetically selected metastatic castration-resistant prostate cancer (mCRPC) patients. A retrospective assessment of 71 patients was performed on platinum use in the Netherlands. Genetically unselected patients yielded low response rates. For a predefined sub-analysis of all patients with comprehensive next-generation sequencing, 30 patients were grouped based on the presence of pathogenic aberrations in genes associated with DNA damage repair (DDR) or aggressive variant prostate cancer (AVPC). Fourtheen patients (47%) were DDR deficient, of which seven with inactivated BRCA2 (BRCA2mut). Six patients classified as AVPC. DDR deficient patients showed beneficial biochemical response to carboplatin, largely driven by all BRCA2mut patients having >50% prostate specific antigen (PSA) decline and objective radiographic response. In the wildtype BRCA2 subgroup, 35% had a > 50% PSA decline (P = 0.006), and 16% radiographic response (P < 0.001). Median overall survival was 21 months for BRCA2mut patients vs seven months (P = 0.041) for those with functional BRCA2. AVPC patients demonstrated comparable responses to non-AVPC, including a similar overall survival, despite the poor prognosis for this subgroup. In the scope of the registration of PARP inhibitors (PARPi) for mCRPC, we provide initial insights on cross-resistance between PARPi and platinum compounds. By combining literature and our study, we identified 18 patients who received both agents. In this cohort, only BRCA2mut patients treated with platinum first (n = 4), responded to both agents. We confirm that BRCA2 inactivation is associated with meaningful responses to carboplatin, suggesting a role for both PARPi and platinum-based chemotherapy in pre-selected mCRPC patients.