HSD3B1 variant shows minimal added value as treatment biomarker in mCRPC
medwireNews: The HSD3B1 CC pathogenic variant does not add prognostic information to standard clinical variables for men receiving abiraterone or enzalutamide for metastatic castration-resistant prostate cancer (mCRPC), study findings indicate.
Elena Castro (Instituto de Investigación Biomédica de Málaga, Spain) and co-investigators therefore say that the HSD3B1 (1245A>C) polymorphism “may not be a suitable stand-alone biomarker in mCRPC.”
The study, published in the Annals of Oncology, included 547 patients from two prospective cohorts who were treated with abiraterone 1000 mg/day plus prednisone 10 mg/day or enzalutamide 160 mg/day.
Overall, 15% of patients carried the HSD3B1 CC genotype (9.4% in cohort 1 and 18.3% in cohort 2). These patients were significantly less likely to achieve a prostate-specific antigen (PSA) reduction of at least 50% than those with the AA or AC genotype, at 48% versus 62% and 65%, respectively.
They also had a significant 31% higher risk for PSA, radiographic, or clinical progression relative to patients with the AA or AC genotypes combined.
However, the association with any progression was attenuated in a multivariate analysis adjusted for standard clinical variables, say Castro et al.
Lactate dehydrogenase and alkaline phosphatase levels above the upper limit of normal, hemoglobin below 10 g/dL, and the use of an androgen receptor pathway inhibitor (ARPI) as first-line therapy for mCRPC were each independently associated with shorter time to any or PSA progression.
There was also no difference between the genotype groups in time to PSA progression or overall survival in either univariate or multivariate analysis.
When the researchers analyzed the data by treatment, they found no significant genotype-related differences in any of the outcomes, and a test for interaction between the HSD3B1 CC genotype and treatment allocation was negative for both time to progression and time to PSA progression.
This indicates “that the CC genotype is not associated with a differential impact on outcomes with abiraterone and enzalutamide,” Castro and team remark.
They also point out that the HSD3B1 CC genotype appeared to have a stronger impact on outcomes in cohort 1 than in cohort 2 and suggest that this could be because the patients in cohort 1 were ARPI naïve whereas those in cohort 2 were not.
“[I]t could be hypothesized that the impact of this polymorphism may be greater in earlier treatment settings where AR-targeted therapies are more active, such as the [metastatic castration-sensitive prostate cancer] setting,” the authors remark.
They conclude: “[B]ased on our results, the CC genotype does not appear to qualify as a useful stand-alone predictive biomarker in the setting of ARPI treatment for mCRPC, and its role must be defined considering other known clinical and genomic prognostic factors.”
In an accompanying editorial, Nima Sharifi, from Cleveland Clinic in Ohio, USA, says that these findings, along with those of another study also reported by medwireNews suggest that “there appears to be a strong and consistent signal that clinical outcomes are worse for men with the HSD3B1 CC genotype after first-line abiraterone or enzalutamide treatment.”
However, she stresses that a number of questions remain unanswered, including how clinical management could potentially be changed for the HSD3B1 CC group, whether knowledge of the genotype should change decision-making for salvage or adjuvant radiotherapy after radical prostatectomy, and what role stereotactic ablative radiation might play.
Sharifi concludes: “Together, these new data help piece together how HSD3B1 as a genetic driver connects biologic states with clinical states of prostate cancer. The relative ease with which germline biospecimens are collected and analyzed should help advance the investigation of how clinicians could intervene with this information earlier in the course of disease.”
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