Platinum-based chemotherapy in metastatic prostate cancer with alterations in DNA damage repair genes.

Abstract

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.