Introduction:

Alterations in DNA damage repair genes can occur in men with advanced prostate cancer (PC) and may impact responses to therapy and clinical outcomes. This study evaluated the prevalence of 8 pathogenic HRR alterations in real-world clinical practice in the United States (US).

Methods:

Clinical data from community oncology and academic centers included in the nationwide (US-based) Flatiron Health-Foundation Medicine, Inc. (FMI) Metastatic PC Clinico-Genomic Database were evaluated (01/01/2013–12/31/2021). De-identified data originated from ~280 US cancer clinics (~800 sites of care). Adult mCPRC patients were included if they had ≥1 line (L) of mCRPC therapy (first receipt = index date), ≥12 mos pre-index clinical activity and ≥1 test for any of the 8 HRR alterations (i.e., short variant, copy number, or rearrangement mutation) included in the MAGNITUDE trial (ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, and/or PALB2; HDAC2 testing not available with FMI data) before or on the index date. Demographic and clinical characteristics, HRR positivity rate (assessed prior to 1L initiation), and time between the first positive test and 1L initiation were described. Individual HRR alteration positivity rates were reported. Flatiron Health, Inc. and FMI did not participate in data analyses.

Results:

A total of 1,150 mCRPC patients had an HRR alteration test prior to initiating a 1L mCRPC therapy (mean age 70.5 years, 67.9% white, 8.6% Black). The median time from mCRPC diagnosis to 1L initiation was 75.5 days. Most common 1L treatments included enzalutamide (30.7%), abiraterone acetate (29.9%), docetaxel (19.7%), sipuleucel-T (8.9%), and radium-223 (5.2%). Overall, 257 patients (22.3%) had ≥1 positive test for any specified HRR alteration, of which 22 (8.6%) had co-occurring alterations. The distribution of specific alterations among HRR positive patients was: CDK12 28.4% (73/257), BRCA2 27.6% (71/257), ATM 25.3% (65/257) and CHEK2 10.9% (28/257); Table. The mean (SD) time between the first positive test for any HRR gene mutation and 1L initiation was 601 (590) days. Most patients (74.7%) were metastatic at the time of first positive test, of which 34.3% were castration-resistant.

Conclusion:

HRR alterations were identified in about 1 in 5 tested patients initiating mCRPC treatment. Future studies should focus on understanding alteration testing strategies in diverse clinical practice settings to ensure patients with HRR alterations are identified in a timely manner and receive appropriate clinical management.

Funding: Janssen Scientific Affairs, LLC