Impact of DNA damage repair (DDR) mutations on treatment outcomes in men receiving conventional therapy for metastatic castration resistant prostate cancer (mCRPC).

Abstract

172 Background: Nearly 25% of patients with mCRPC harbor DDR alterations, with some of these mutations associating with increased tumor susceptibility to PARP inhibitors and platinum-based chemotherapies. While, mutations in some DDR genes (e.g. BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating DDR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ASIs) or taxane-based chemotherapy have yielded conflicting results. Methods: We conducted a single center retrospective analysis to assess clinical outcomes to standard therapies in mCRPC patients with/without DDR mutations as determined on clinical grade next-generation sequencing assays. The primary endpoint was PSA50 response (i.e. ≥50% PSA reduction from baseline), estimated using Bayesian logical regression; secondary endpoints included PSA progression-free survival (PFS), estimated using Kaplan-Meier methods. Results: A total of 93 patients were included in this analysis, with DDR mutations identified in 40/93 (43%). No significant correlations were found between DDR status and PSA50 response within treatment modalities even after adjusting for receipt of prior therapies within the same class (Table). DDR status was not associated with PSA PFS in patients treated with ASIs. There was evidence of decreased PFS in patients with BRCA1/2 and PALB2 mutations treated with Docetaxel (p = 0.008) and Cabazitaxel (p = 0.005), but limited patient numbers precluded significant pairwise analysis with Cabazitaxel. Conclusions: DDR gene mutational status was not associated with inferior clinical outcomes following treatment with ASIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.[Table: see text]