Comparison of Real-World Outcomes between Patients with BRCA1/2-Positive and Homologous Recombination Repair-Negative Metastatic Castration-Sensitive Prostate Cancer

Adv Ther. 2025 Aug;42(8):3945-3959. doi: 10.1007/s12325-025-03270-z. Epub 2025 Jun 17.

Abstract

Introduction: This real-world study compared time-to-next-treatment (TTNT), time-to-castration resistance (TTCR), and overall survival between patients with BRCA1/2-positive (BRCA+) and homologous recombination repair-negative (HRR-) metastatic castration-sensitive prostate cancer (mCSPC).

Methods: Patients who received a genetic test and initiated treatment for mCSPC (index date) after 1/1/2018 were selected from the Flatiron Health-Foundation Medicine, Inc. Metastatic PC Clinico-Genomic Database (1/1/2017-12/31/2022). Outcomes were compared between patients with ≥ 1 positive BRCA test (BRCA+) and those without detected HRR mutations (HRR-) using weighted Kaplan-Meier analyses and Cox proportional hazards models after baseline characteristics (12 months pre-index) were balanced using inverse-probability of treatment weighting.

Results: In total, 149 patients with BRCA+ and 1066 with HRR- mCSPC were included. Baseline characteristics were well-balanced after weighting. By 24 months after treatment initiation, a significantly higher proportion of the BRCA+ than the HRR- cohort progressed to next treatment [69.7% vs. 56.8%; hazard ratio (HR) = 1.45 (95% confidence interval (CI) 1.10, 1.92), p = 0.009]; median TTNT was shorter in the BRCA+ than the HRR- cohort (10.9 vs. 18.7 months). By 24 months, a significantly higher proportion of the BRCA+ than the HRR- cohort progressed to castration resistance [72.2% vs. 61.4%; HR = 1.46 (95% CI 1.16, 1.84), p = 0.001]; median TTCR was shorter in the BRCA+ than HRR- cohort (12.9 vs. 16.9 months). Numerically fewer patients in the BRCA+ than the HRR- cohort survived 24 months after PC diagnosis [80.6% vs. 85.4%; HR = 1.46 (95% CI 0.99, 2.14), p = 0.054].

Conclusion: Findings demonstrate worse outcomes for patients with BRCA+ mCSPC treated with available advanced therapies, supporting the need for effective genetically targeted therapies in this population.

Keywords: BRCA; Homologous recombination repair; Metastatic castration-sensitive; Overall survival; Prostate cancer; Time-to-castration resistance; Time-to-next-treatment.

Publication types

  • Comparative Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • BRCA1 Protein* / genetics
  • BRCA2 Protein* / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / mortality
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Prostatic Neoplasms, Castration-Resistant* / therapy
  • Recombinational DNA Repair
  • Retrospective Studies
  • Time-to-Treatment

Substances

  • BRCA2 Protein
  • BRCA1 Protein
  • BRCA2 protein, human
  • BRCA1 protein, human