Time-to-next treatment (TTNT) and overall survival (OS) among homologous recombination repair (HRR) positive and HRR negative patients with metastatic castration-resistant prostate cancer (mCRPC) initiating first-line (1L) therapy.
Authors: Bilen Mehmet Asim , Khilfeh Ibrahim , Rossi Carmine , Muser Erik , Morrison Laura , Hilts Annalise , Waters Dexter , Lefebvre Patrick , Pilon Dominic , George Daniel J. 
Published: March 2023

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Background: Several recurrent mutations that interfere with the HRR DNA damage signaling response pathway have been recently identified as novel biomarkers that may help optimize treatment for patients with mCRPC. There is limited real-world information on clinical outcomes, including TTNT and OS, among patients with mCRPC who initiate 1L, overall and by HRR mutation status in the United States. Methods: This study used the nationwide (de-identified) Flatiron Health – Foundation Medicine Inc. (FMI) Metastatic Prostate Cancer Clinico-Genomic Database (1/1/2011–12/31/2021). The de-identified data originated from approximately 280 US cancer clinics (~800 care sites). Patients who initiated 1L therapy (index date) on or after mCRPC diagnosis and had ≥1 HRR mutation test any time prior to or on the index date were included. Patients were excluded if they initiated a clinical trial drug in 1L or had <12 months of clinical activity before the index date. Patients were classified as HRR+ (i.e., ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2) or HRR-. HRR+ pathogenic mutations were any qualifying short variant, copy number loss, or rearrangement mutations. For TTNT, patients were followed from index date until the earliest of 2L initiation (outcome), end of clinical activity (including death) or end of data availability. For OS, patients were followed from index date until the earliest of death (outcome), end of clinical activity, or end of data availability. For both outcomes, HRR- patients were censored at first HRR+ mutation test. TTNT and OS were reported overall and by baseline HRR status using Kaplan-Meier methods. Flatiron Health and FMI did not participate in data analyses. Results: A total of 1,150 tested patients with mCRPC who initiated 1L therapy were included (mean age 70 years, 68% white, 59% initiated 1L on or after 2019). Overall, 257 patients (22%) were HRR+ by 1L initiation, of which 82 (7% overall) had a BRCA1/2 mutation. Overall, enzalutamide (31%), abiraterone acetate (30%), and docetaxel (20%) were the most used medications in 1L. The median TTNT was 8.0 months, overall, and was numerically shorter for HRR+ (6.8 months) than HRR- (8.2 months). Overall, 2L initiation rates were 15% at 3 months (HRR+: 17%; HRR-: 15%), 38% at 6 months (HRR+: 45%; HRR-: 36%), and 64% at 12 months (HRR+: 69%; HRR-: 62%). The median OS time was 24.9 months, overall, and was numerically shorter for HRR+ (23.0 months) compared to HRR- (25.8 months) patients. Overall, survival rates were 91% at 6 months (HRR+: 93%; HRR-: 91%), 78% at 12 months (HRR+: 75%; HRR-: 79%), and 51% at 24 months (HRR+: 47%; HRR-: 53%). Conclusions: Patients with HRR+ mCRPC were observed to have shorter survival and progress more rapidly from 1L to 2L therapy than HRR- patients, suggesting greater unmet need in these patients.