In patients with castration-resistant prostate cancer (CRPC), a variant of the HSD3B1 gene predicts sensitivity to the CYP17A1 inhibitor ketoconazole, according to results of a single-center, observational study including 90 men treated between June 1998 and December 2012.

Median progression-free survival (PFS) increased along with the number of variant HSD3B1(1245C) alleles, wrote Nima Almassi, MD, of the Cleveland Clinic, and coauthors (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3159 ).

Specifically, median PFS was just 5.0 months for patients with no variant HSD3B1(1245C) alleles, 7.5 months for patients with one allele, and 12.3 months for those with two alleles (P = .03).

“These findings suggest that the variant allele … may be a predictive biomarker of tumor vulnerability to pharmacologic CYP17A1 inhibition with a nonsteroidal drug,” Dr. Almassi and colleagues wrote.

The HSD3B1(1245C) germline variant was already known in the prostate cancer research community as a marker of tumor resistance to androgen deprivation therapy (ADT) and more rapid disease onset. In a separate study published in the same issue (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3164 ) investigators provided additional evidence, showing that the genotype was associated with more rapid metastasis development in men with localized prostate cancer who received ADT for biochemical recurrence after radiation treatment.

In that observational study of 218 men treated between 1996 and 2003, median time to metastasis (TTM) decreased according to the number of inherited variant alleles, wrote Jason W. D. Hearn, MD, University of Michigan, Ann Arbor, and coauthors. Those with no variant HSD3B1(1245C) alleles had a TTM of 7.4 months, while those with one allele had a TTM of 5.8 months, and for those with two, TTM was only 4.4 months (P = .03).

However, investigators could not detect any such relationship between variant HSD3B1(1245C) alleles and time to progression (TTP) or overall survival (OS): “It is possible that the high rates of prior ADT exposure and frequent use of androgen receptor (AR) antagonists during salvage ADT modified the impact of genotype with respect to composite TTP and OS,” Dr. Hearn and colleagues wrote. “Nonetheless, the large impact on TTM is statistically and clinically significant.”

While the findings of Dr. Hearn and colleagues bolster existing knowledge that variant HSD3B1(1245C) alleles are associated with poorer outcomes in prostate cancer, the findings from Dr. Almassi and colleagues add new insights regarding the potential role of CYP17A1 inhibitors in patients with this genotype.

“As only a proportion of patients treated with potent CYP17A1 inhibitors or AR antagonists respond clinically, a predictive biomarker for the identification of patients who benefit would undoubtedly have clinical value,” Dr. Almassi and colleagues said.

The findings are somewhat limited, however, because they were focused on ketoconazole, a nonsteroidal CYP17A1 inhibitor that is no longer routinely used in clinic for prostate cancer.

Similar studies of the steroidal CYP17A1 inhibitor abiraterone acetate would be possible, however, “steroidal metabolites of [steroidal CYP17A1 inhibitors] make evaluation more complex,” Dr. Almassi and colleagues wrote.


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