The significance of androgen receptor signaling pathway in mCRPC patients receiving olaparib monotherapy or combined treatment with abiraterone.

Abstract

197 Background: Our previous research confirmed that for metastatic castration-resistant prostate cancer (mCRPC) patients with DNA damage repair (DDR) deficiency who have developed resistance to prior abiraterone, the combination of olaparib and abiraterone improves survival compared to olaparib monotherapy. However, further research is needed to identify subgroups who may benefit from olaparib alone or in combination with abiraterone, and to pinpoint risk factors significantly associated with poor prognosis in these patients. This study aims to explore the value of androgen receptor (AR) variant and androgen receptor activity (AR-A) at the transcriptomic level in evaluating the prognosis of mCRPC patients treated with olaparib alone or in combination with abiraterone. Methods: This study included 142 mCRPC patients who underwent targeted next-generation sequencing. Among them, 73 patients received olaparib monotherapy, while 69 patients received combined therapy. Bulk transcriptome sequencing was performed for 62 patients. Kaplan-Meier analysis was employed to evaluate patients' progression-free survival (PFS) and overall survival (OS). The AR-A score was calculated through a weighted linear sum of nine typical AR transcriptional target genes. Results: The combination of olaparib and abiraterone significantly improved PSA response and survival (PFS and OS) compared to olaparib monotherapy. Among mCRPC patients receiving olaparib monotherapy, those without AR pathogenic variant (AR-PV) had superior PFS and OS compared to those with AR-PV (median PFS: 5 months vs 3 months; median OS: 23 months vs 17 months). At the transcriptome level, for mCRPC patients receiving combined therapy, the average AR-A group exhibited better PFS and OS compared to the lower AR-A group (median PFS: 7 months vs 3 months; median OS: 17 months vs 10 months). Conclusions: For mCRPC patients treated with olaparib monotherapy, the absence of AR-PV can obtain better survival benefits. For patients treated with combined therapy, the average AR-A indicates a better survival benefit. For mCRPC patients with AR-PV or lower AR-A score, large-scale prospective randomized controlled clinical trials are needed to further explore therapy strategies that can improve their prognosis.