Are Germline DNA Repair Mutations Linked to Outcomes in mCRPC?

Germline BRCA2 status may be of assistance to clinicians when determining initial treatment for men with metastatic castration-resistant prostate cancer (mCRPC), according to a new study published in the Journal of Clinical Oncology.

It is well-established that germline mutations in DNA damage repair (gDDR) genes affect a significant proportion of patients with mCRPC. However, the clinical implications of this finding have remained unclear.

“This study is important because it brings us one step closer to the incorporation of these tests into clinical practice. Not only does germline screening have the potential to guide treatment selection, as in this study, but to also improve patient selection for prostate cancer screening and decisions for biopsy and treatment,” said urologic oncologist Daniel Oberlin, MD, of Golden Gate Urology in San Francisco, in an interview with Cancer Network.

Oberlin also noted that huge advancements in genetic sequencing technologies over just the last 10 years have significantly improved the ability to study the genetic influencers of prostate cancer.

Elena Castro, MD, PhD, of the Spanish National Cancer Research Center in Madrid, and colleagues prospectively enrolled unselected patients with mCRPC and screened them for gDDR mutations in 107 genes. They then examined the impact of ATM/BRCA1/BRCA2/PALB2 germline mutations on cause-specific survival (CSS).

The association between gDDR subgroups and response outcomes for mCRPC treatments was also evaluated. As part of the investigation, the researchers explored combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2).

Of 419 eligible patients, 68 carriers were identified (16.2%); of these, 14 had mutations in BRCA2, 8 had mutations in ATM, 4 had mutations in BRCA1, and none had PALB2 mutations. The study was not able to reach its primary endpoint because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and non-carriers was not statistically significant. However, CSS was approximately 50% lower in germline BRCA2 (gBRCA2) carriers vs non-carriers (17.4 vs 33.2 months, respectively). 

Significant interactions were found between gBRCA2 status and treatment type (androgen signaling inhibitor vs taxane therapy). CSS was 24.0 months in gBRCA2 carriers treated with abiraterone or enzalutamide as first-line therapy compared with 17.0 months for those treated with taxanes. PFS2 was 18.9 months in gBRCA2 carriers treated first-line with abiraterone or enzalutamide compared with 8.6 months with taxanes. The study showed no differences in clinical outcomes by treatment type in non-carriers.

The results of this study suggest that outcomes associated with gBRCA2 may be modified by the initial treatment approach, according to the researchers. They theorized that gBRCA2 mutations have a deleterious impact on mCRPC outcomes, but may be affected by treatment type as well as by treatment sequence. However, these findings are based on only a small number of patients and require additional validation, they concluded.