1. Treatment with abiraterone and enzalutamide does not overcome poor outcome from metastatic castration-resistant prostate cancer in men with the germline homozygous HSD3B1 c.1245C genotype
- Author
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David Dolling, Claudia Bertan, Adam Sharp, W.B. Isaacs, Suzanne Carreira, Angelika Terbuch, Jun Yu, Ying Chen, Jun Luo, Emmanuel S. Antonarakis, Hao Wang, Changxue Lu, J.S. de Bono, and J. Fountain
- Subjects
0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Genotype ,Abiraterone Acetate ,Steroid Isomerases ,Androgen deprivation therapy ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Multienzyme Complexes ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,Medicine ,Enzalutamide ,Humans ,Retrospective Studies ,business.industry ,Progesterone Reductase ,Hazard ratio ,Androgen Antagonists ,Hematology ,Prostate-Specific Antigen ,medicine.disease ,Confidence interval ,Log-rank test ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Germ Cells ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Cohort ,Benzamides ,Androstenes ,business - Abstract
Background In men with castration-sensitive prostate cancer (CSPC), the HSD3B1 c.1245A>C variant has been reported to be associated with shorter responses to first-line androgen-deprivation therapy (ADT). Here, we evaluated the association between the inherited HSD3B1 c.1245A>C variant and outcomes from metastatic castration-resistant prostate cancer (mCRPC) after first-line treatment with abiraterone (Abi) or enzalutamide (Enza). Patients and methods Patients with mCRPC (n = 266) were enrolled from two centers at the time of starting first-line Abi/Enza. Outcomes after Abi/Enza included best prostate-specific antigen (PSA) response, treatment duration, and overall survival (OS). Outcomes after first-line ADT were determined retrospectively, and included treatment duration and OS. As was prespecified, we compared patients with the homozygous variant HSD3B1 genotype (CC genotype) versus the combined group with the heterozygous (AC) and homozygous wild-type (AA) genotypes. Results Among the 266 patients, 22 (8.3%) were homozygous for the HSD3B1 variant (CC). The CC genotype had no association with PSA response rate; the median Abi/Enza treatment duration was 7.1 months for the CC group and 10.3 months for the AA/AC group (log rank P = 0.34). Patients with the CC genotype had significantly worse OS, with median survival at 23.6 months for the CC group and 30.7 months for the AA/AC group (log rank P = 0.02). In multivariable analysis adjusting for age, Gleason score, PSA, prior chemotherapy, and M1 disease, the association between the CC genotype and OS remained significant (hazard ratio 1.78, 95% confidence interval 1.03–3.07, P = 0.04). Poor outcome after first-line ADT in the CC group was also observed when evaluating retrospective ADT duration data for the same combined cohort. Conclusions In this large two-center study evaluating the HSD3B1 c.1245 genotype and outcomes after first-line Abi/Enza, homozygous variant (CC) HSD3B1 genotype was associated with worse outcomes. Novel therapeutic strategies are needed to enable treatment selection based on this genetic marker.
- Published
- 2019