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

C. Lu, A. Terbuch, D. Dolling, J. Yu, H. Wang, Y. Chen, J. Fountain, C. Bertan, A. Sharp, S. Carreira, W. B. Isaacs, E. S. Antonarakis, J. S. De Bono, J. Luo

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1178-1185
Number of pages8
JournalAnnals of Oncology
Volume31
Issue number9
DOIs
StatePublished - Sep 2020
Externally publishedYes

Bibliographical note

Funding Information:
We thank the study participants and their families. None declared. AS received travel support from Roche-Genentech and Sanofi; Speakers honorarium from Astellas Pharma; Support from Prostate Cancer Foundation Young Investigator Award. ESA receives honorarium from Sanofi, Dendreon, Medivation, Janssen Pharmaceuticals, ESSA, Astellas Pharma, Merck, AstraZeneca, and Clovis Oncology; Research Funding from Janssen Biotech (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst), Millennium Pharmaceuticals (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), and Constellation Pharmaceuticals (Inst); and is a co-inventor of a biomarker technology that has been licensed to QIAGEN. JSdB has served on advisory boards for many companies including Astra Zeneca, Astellas, Bayer, Boehringer Ingelheim, Genentech/Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Sanofi Aventis, and Taiho. The ICR have a commercial interest in abiraterone, PARP inhibition in DNA repair-defective cancers, and PI3K/AKT pathway inhibitors (no personal income). The ICR have received funding or other support for my research work from AZ, Astellas, Bayer, Genentech, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Taiho. JSdB has been the CI/PI of many industry-sponsored clinical trials. JL has served on advisory boards for Sun Pharmaceutical Industries, Tolero Pharmaceuticals, and Janssen Oncology; received Research Funding from Sanofi (Inst), Orion Pharma (Inst), Mirati Therapeutics (Inst), Gilead Sciences (Inst), Astellas Pharma (Inst), Constellation Pharmaceuticals (Inst); and is a co-inventor of a technology assigned to Johns Hopkins University who licensed to Tokai Pharmaceuticals (Inst), co-inventor of a technology licensed to QIAGEN (Inst), co-inventor of a technology licensed to A&G Pharmaceuticals (Inst). CL is a co-inventor of a technology that has been licensed to Tokai and Qiagen. All remaining authors have declared no conflicts of interest.

Funding Information:
AS received travel support from Roche-Genentech and Sanofi; Speakers honorarium from Astellas Pharma; Support from Prostate Cancer Foundation Young Investigator Award. ESA receives honorarium from Sanofi, Dendreon, Medivation, Janssen Pharmaceuticals, ESSA, Astellas Pharma, Merck, AstraZeneca, and Clovis Oncology; Research Funding from Janssen Biotech (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst), Millennium Pharmaceuticals (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), and Constellation Pharmaceuticals (Inst); and is a co-inventor of a biomarker technology that has been licensed to QIAGEN. JSdB has served on advisory boards for many companies including Astra Zeneca, Astellas, Bayer, Boehringer Ingelheim, Genentech/Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Sanofi Aventis, and Taiho. The ICR have a commercial interest in abiraterone, PARP inhibition in DNA repair-defective cancers, and PI3K/AKT pathway inhibitors (no personal income). The ICR have received funding or other support for my research work from AZ, Astellas, Bayer, Genentech, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Taiho. JSdB has been the CI/PI of many industry-sponsored clinical trials. JL has served on advisory boards for Sun Pharmaceutical Industries, Tolero Pharmaceuticals, and Janssen Oncology; received Research Funding from Sanofi (Inst), Orion Pharma (Inst), Mirati Therapeutics (Inst), Gilead Sciences (Inst), Astellas Pharma (Inst), Constellation Pharmaceuticals (Inst); and is a co-inventor of a technology assigned to Johns Hopkins University who licensed to Tokai Pharmaceuticals (Inst), co-inventor of a technology licensed to QIAGEN (Inst), co-inventor of a technology licensed to A&G Pharmaceuticals (Inst). CL is a co-inventor of a technology that has been licensed to Tokai and Qiagen. All remaining authors have declared no conflicts of interest.

Publisher Copyright:
© 2020 European Society for Medical Oncology

Keywords

  • HSD3B1
  • abiraterone
  • androgen-deprivation therapy
  • biomarker
  • enzalutamide
  • mCRPC

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