medwireNews: Germline mutations in the BRCA2 gene, but not other DNA damage repair (DDR) genes, are associated with poorer outcomes among patients with metastatic castration-resistant prostate cancer (mCRPC), study findings indicate.
Furthermore, the impact of germline BRCA2 mutations on outcome may be affected by the type of first-line treatment used, report David Olmos (Spanish National Cancer Research Center, Madrid) and PROREPAIR-B study co-authors.
The PROREPAIR-B study assessed the clinical implications of germline mutations in ATM, BRCA1, BRCA2, and PALB2 – the most frequently mutated genes detected in men with mCRPC – in 419 patients with mCRPC.
The men were screened for germline mutations in 107 DDR genes overall, with 68 (16.2%) carriers identified. Of these 14 had a BRCA2 mutation, eight carried a ATM mutation, and four had a BRCA1 mutation. None of the patients carried a PALB2 mutation.
The researchers found that although cause-specific survival (CSS) was numerically lower among ATM/BRCA1/BRCA2/PALB2 germline mutation carriers than noncarriers, at a median 23.3 versus 33.2 months, the difference was not statistically significant.
However, when each mutation was analyzed separately, median CSS was significantly shorter among germline BRCA2 mutation carriers than noncarriers, at 17.4 versus 33.2 months, with a significant hazard ratio for prostate cancer-specific death of 2.11.
Olmos and co-investigators also identified a significant interaction between germline BRCA2 status and treatment type (androgen signaling inhibitor [ASI] vs taxane therapy), whereby BRCA2 mutation carriers had significantly worse outcomes than noncarriers when treated with taxanes as first-line therapy but not when they received an ASI as their first treatment.
Specifically, median CSS was 10.7 and 28.4 months among germline BRCA2 carriers and noncarriers, respectively, treated with a taxane–ASI sequence, but 24.0 and 31.2 months, respectively, among those treated with an ASI–taxane sequence.
And a similar pattern was observed when the team looked at the progression-free survival time from initiation of first-line therapy to progression to second-line therapy or death.
Writing in the Journal of Clinical Oncology, Olmos et al caution that although their findings “suggest that the outcomes associated with [germline] BRCA2 may be modified by the initial treatment type,” the “observation is based on a small number of patients and requires additional validation before a change in clinical practice is supported.”
“However, if confirmed, [germline] BRCA2 would be the first genetic biomarker to select an ASI instead of taxanes as the first line of treatment for mCRPC,” the authors conclude.
By Laura Cowen
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