DNA-Damaging Therapies in Patients With Prostate Cancer and Pathogenic Alterations in Homologous Recombination Repair Genes.

Abstract

Outcomes data for DNA-damaging therapeutics for men with prostate cancer (PC) and non-<i>BRCA1/2</i> homologous recombination repair (HRR) mutations are limited. We evaluated outcomes by HRR alteration in men with PC treated with poly(ADP-ribose)polymerase inhibitors (PARPi) and/or platinum chemotherapy. Retrospective data from the PROMISE consortium were used. Clinical outcomes differences were assessed between patients with <i>BRCA1</i>/<i>2</i> mutations (cohort A) and those with HRR mutations without direct BRCA complex interaction (cohort B: <i>ATM</i>, <i>CDK12</i>, <i>CHEK1</i>, <i>CHEK2</i>, and <i>FANCL</i>). Outcomes in patients with HRR mutations with direct BRCA complex interaction were also explored (cohort C: <i>RAD51B/C/D</i>, <i>RAD54L2</i>, <i>BARD1</i>, <i>GEN1</i>, <i>PALB2</i>, <i>FANCA</i>, and <i>BRIP1</i>). One hundred and forty-six patients received PARPi (cohort A: 94, cohort B: 45, cohort C: 7) and 104 received platinum chemotherapy (cohort A: 48, cohort B: 44, cohort C: 10). PSA50 response rate to PARPi was higher in cohort A (61%) than cohort B (5%), <i>P</i> < .001. Median clinical/radiographic progression-free survival (crPFS) with PARPi in cohort A was significantly longer than in cohort B: 15.9 versus 8.7 months, <i>P</i> = .005. PSA50 response rate to platinum therapy was higher in cohort A (62%) than in cohort B (32%), <i>P</i> = .024, although crPFS was not significantly different. PSA50 response rate to PARPi and platinum was 40% and 32%, respectively, in cohort C. In multivariable analysis, cohort A had significantly improved overall survival and crPFS compared with cohort B with PARPi but not platinum chemotherapy. Patients with <i>BRCA1/2</i>-mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.