BRCA-Altered mCSPC Progresses Faster on ARPIs: A Real-World Treatment Gap

Recent real-world data clarify how homologous recombination repair (HRR) alterations, especially BRCA1/2 mutations, affect outcomes in metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen receptor pathway inhibitors (ARPIs). In a US cohort of 745 patients, overall differences in time-to-next-treatment (TTNT) and time-to-castration resistance (TTCR) were modest between patients without HRR alterations and those with non-BRCA HRR alterations.
However, patients with BRCA1/2 mutations showed markedly faster progression. Their median TTNT was 19.6 months compared with 24.9 months for other HRR-altered patients and 27.2 months for those without HRR alterations. Similarly, median TTCR was 20.1 months in BRCA1/2-positive patients versus 24.7 months and 28.1 months in the other groups. By 24 months, nearly 60 percent of BRCA1/2-positive patients required a next treatment and more than half had developed castration resistance, compared with roughly 46 to 49 percent in the other groups.

These findings reinforce what is already known from the castration-resistant setting: BRCA1/2 alterations drive a more aggressive, ARPI-resistant biology. The important new insight is that this disadvantage is already present in mCSPC, before patients become castration-resistant. For patients without BRCA1/2 mutations, current ARPI-based approaches appear adequate, with no major difference in outcomes between HRR-negative and non-BRCA HRR-positive disease.

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