A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in metastatic hormone sensitive prostate cancer patients with HRR gene mutation: Updated analysis of PROact.

Abstract

TPS292 Background: Approximately 10% - 15% of patients with metastatic hormone sensitive prostate cancer (mHSPC) harbor loss-of-function mutations in homologous recombination repair (HRR) genes. Although olaparib plus abiraterone and prednisone has significantly prolonged radiographic progression-free survival (rPFS) in metastatic castration resistant prostate cancer patients, there is a lack of evidence regarding the efficacy of this combination therapy in patients with mHSPC. Here, we report the updated analysis of PROact study, the first phase II trial to evaluate the effects of olaparib plus abiraterone and prednisone in mHSPC patients with HRR gene mutation. Methods: This was a single center, single arm, phase II trial (NCT05167175) conducted in male patients with mHSPC who had at least one HRR gene mutation ( BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51D and RAD54L ) as determined by tissue-NGS. Patients were administered olaparib 300 mg BID plus abiraterone 1000 mg QD and prednisone 5 mg QD. Previous treatment with new hormonal agent (NHA) was not allowed. The primary endpoint was 1-year radiographic progression-free survival (rPFS) rate per PCWG3-modified RECIST 1.1 by investigator assessment. The secondary endpoint included prostate-specific antigen (PSA) response rate, objective response rate (ORR), and adverse events. Safety and efficacy data with a median follow-up of 9.5 months have been reported. Here, we present the updated efficacy data categorized by gene. Results: Thirty patients were enrolled, all of whom had de novo mHSPC, consisting of 30% (9/30) with low-volume and 70% (21/30) with high-volume disease. As of the data cut-off (September 6, 2024), the median follow-up duration was 14.0 months. 13 patients had measurable disease; the confirmed ORR was 84.6% (11/13). One patient with ATM mutation achieved complete response. Ten patients obtained partial response, including four with BRCA2 , two with ATM , two with CDK12 , one with RAD51B mutations and one with co-mutation of three pathogenic genes. Furthermore, two patients harboring BRCA2 mutation experienced progressive disease (Table). Clinical trial information: NCT05167175 . Gene by gene efficacy evaluation. HRR mutation Totally number RECIST assessment CR PR PD BRCA2 11 6 0 4 2 CDK12 7 2 0 2 0 ATM 6 3 1 2 0 PALB2 2 0 - - - CHEK2 1 0 - - - RAD51B 1 1 0 1 0 RAD51D 1 0 - - - CDK12, CHEK2, RAD51B 1 1 0 1 0