Real-World Analysis Reveals Gaps in HRR Testing and PARP Inhibitor Treatment in mCRPC

Clinical practice gaps in the management of metastatic castration-resistant prostate cancer (mCRPC) include a lack of germline or somatic testing, delayed homologous recombination repair (HRR) testing, and delayed PARP inhibitor therapy, according to data from an extended real-world analysis that were presented at the 2025 Genitourinary Cancers Symposium.1

In total, 81% of patients included in the analysis (n = 1022) did not receive HRR testing at the time of diagnosis, and 35% of patients who tested positive for HRR mutations received treatment with PARP inhibitors before the third line of therapy.

“This extended real-world analysis confirms clinical practice gaps in the clinical management of [patients with] mCRPC, demonstrating lack of or delayed biomarker testing and PARP [inhibitor] treatment,” the researchers wrote in the poster. “Continuing education and standardized testing practices may be needed to address these gaps.”

Germline and Somatic Testing

Of the patients with mCRPC included in this analysis, 63.6% (n = 650) underwent HRR mutation testing, including germline testing (21.2%; n = 138); somatic testing (58.8%; n = 382); both germline and somatic testing 3.4%; n = 22); and unknown testing 16.6%; n = 108).

Regarding test timing, 19% (n = 122) of patients underwent testing at the time of diagnosis; 41% (n = 265) of patients received testing during or after the first line of treatment; 22% (n = 145) of patients underwent testing during or after the second line of treatment; and 18% (n = 118) of patients received testing after 3 or more lines of treatment. Nine percent (n = 56) of patients had testing failure, of whom 38% (n = 21) experienced failures from somatic tissue testing.

Testing identified that 38% (n = 226) of patients included in this analysis were HRR mutation positive. Approximately half of these patients—58.4% (n = 132)—were treated with a PARP inhibitor. This included 13 patients who received a PARP inhibitor after more than 1 line of therapy and 23% (n = 33) of patients who received a PARP inhibitor plus next-generation hormonal agent combination therapy. Of note, 65% (n = 95) of patients who received PARP inhibitors were treated with a PARP inhibitor after more than 3 lines of treatment.

In patients treated with PARP inhibitors, the HRR mutation–positive genes included ATM (30.9%; n = 47); BRCA2 (33.6%; n = 51); BRCA1 and CDK12 (6.6%; n = 10); CHEK2 (13.2%; n = 20); RAD54L (2%; n = 3); PALB2 (5.3%; n = 8); and CHEK1, BRIP1, or RAD51B (0.7%; n = 1).

Among the 94 patients who were not treated with a PARP inhibitor, 15.9% (n = 17) were BRCA2 positive, 29% (n = 31) were ATM positive, and 3.7% (n = 4) were BRCA1 positive.

“It is particularly concerning that not all BRCA1/2- and ATM-positive patients receive PARP [inhibitor] therapy,” the researchers wrote in the abstract.

Study Background

According to the study’s background, testing for HRR mutations is standard of care for all patients with mCRPC as a way to identify who is eligible for treatment with PARP inhibitors. A previous real-world analysis conducted by this team from January 1, 2020, to December 31, 2021, demonstrated that 40.8% of patients with mCRPC did not receive HRR mutation testing. In addition, the previous analysis showed that 33.2% of patients who tested positive for HRR mutations were not treated with a PARP inhibitor.

“The approval of novel hormonal therapies in combination with PARP [inhibitors] for first-line treatment of mCRPC prompted us to expand our analysis, to determine timing of HRR mutation testing in relation to line of therapy initiated, [line of therapy] when [novel hormonal therapies] and/or PARP [inhibitors] were received, and breakdown of HRR mutation[–positive] genes in PARP [inhibitor] treated and untreated cohorts,” the researchers wrote in the abstract.

To perform this current analysis, researchers used the IntegraConnect – Precision Q deidentified database, which consisted of electronic health and practice management data from 500 United States sites of care. Researchers identified a real-world cohort of patients with newly diagnosed or treated mCRPC between January 1, 2020, and December 31, 2023. Medical curators manually reviewed patient charts to extract data, such as testing success rate and results, timing and frequency of germline and somatic testing for HRR mutations, and line of therapy where novel hormonal therapies and/or PARP inhibitors were received in the patients who tested positive for HRR mutations.

Reference

Shore ND, Vasudevan A, Li J, et al. Real-world clinical practice gaps in timely homologous recombination repair gene mutation (HRRm) testing and poly (ADP-ribose) polymerase inhibitor (PARPi) treatment of patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2025;43(suppl 5):85. doi:10.1200/JCO.2025.43.5_suppl.85