medwireNews: Men with metastatic castration-resistant prostate cancer (mCRPC) who carry the CC genotype of the HSD3B1 c.1245A>C variant have worse responses to first-line abiraterone and enzalutamide than those with an AA or AC genotype, research shows.
The HSD3B1 c.1245A>C variant has previously been associated with a poor response to androgen deprivation therapy (ADT) in men with metastatic castration-sensitive prostate cancer but the results among men with mCRPC have been conflicting.
Furthermore, it has been hypothesized that this poor prognosis could be overcome by treatment with CYP17A1 inhibitors such as abiraterone or potent antiandrogens such as enzalutamide.
To investigate, Jun Luo (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) and team studied 266 patients with mCRPC who were starting first-line therapy with abiraterone or enzalutamide. Of these, 8.3% were homozygous for the HSD3B1 CC variant.
Compared with individuals who had the AA or AC genotype, those with the CC genotype had significantly shorter median overall survival, at 23.6 versus 30.7 months, and a hazard ratio for death of 1.78 after adjustment for age, Gleason score, prostate-specific antigen (PSA), prior chemotherapy, and M1 disease.
By contrast, the two groups had similar PSA response rates with 68.4% and 67.7% of those in the CC and AA/AC groups, respectively, experiencing a PSA decline of at least 30%, and 57.9% and 59.5%, respectively, recording a decline of at least 50%.
“This discrepancy in different outcome measures suggest that patients with the CC genotype may represent a general poor prognosis group given the lack of evidence supporting differential treatment effect measured by PSA response,” Luo et al remark in the Annals of Oncology.
The median treatment duration of 7.1 months in the CC group was not significantly different from that of 10.3 months in the AA/AC group.
The researchers also conducted a post-hoc analysis of outcomes in the same cohort after ADT therapy. They found that those with the CC genotype had shorter first-line ADT duration (14.0 vs 18.0 months) and median overall survival from the time of first-line ADT (57.7 vs 80.8 months) than those with the AA or AC genotype, but the differences were not statistically significant after adjusting for potential confounders.
Luo and co-authors say that they “did not uncover evidence supporting the upfront use of [abiraterone and enzalutamide] for the purpose of overcoming poor response to first-line ADT predicted by [HSD3B1 c.1245A>C].”
They add: “Instead, patients with the CC genotype have worse overall survival following [abiraterone and enzalutamide].”
Therefore, “[n]ovel therapeutic strategies are needed to enable treatment selection based on this genetic marker,” they conclude.
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