Heterogeneity and synergistic inhibition of the poly(ADP-ribose) polymerase and androgen receptor signaling pathway in patients with metastatic castration-resistant prostate cancer.

Abstract

236 Background: Our previous study demonstrated that olaparib combined with abiraterone improves survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, compared with olaparib monotherapy. However, reliable biomarkers are urgently needed to identify patients who are more likely to benefit from olaparib treatment, particularly in the context of combination therapy. Methods: A total of 221 consecutive mCRPC patients were included, including 135 who received olaparib combined with abiraterone and 86 who received olaparib monotherapy. The predictive value of PARP1 mRNA expression and androgen receptor (AR) signaling biomarkers (AR activity [AR-A] and AR pathogenic variants [AR-PV]), was evaluated across single-cell RNA, bulk RNA, and DNA levels in relation to olaparib treatment outcomes. Results: PARP1 and AR-A exhibited marked heterogeneity in mCRPC. In tumor cells, PARP1 expression was significantly positively correlated with AR-A score. Compared with olaparib monotherapy, olaparib combined with abiraterone significantly improved progression-free survival (PFS) and overall survival (OS) in mCRPC patients, particularly among those harboring a PARP1 high /AR-A high signature or a BRCA variants/AR-nPV signature. Conclusions: Biomarkers reflecting DNA damage repair deficiency and AR signaling have potential value in guiding the selection of mCRPC patients for olaparib treatment, particularly in the context of combination therapy. Patients harboring a PARP1 high /AR-A high signature or a BRCA variants/AR-nPV signature are more likely to benefit from olaparib combined with abiraterone or olaparib monotherapy. These findings warrant further validation through prospective clinical trials.