Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial.

BACKGROUND

The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined.

PATIENTS AND METHODS

Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC.

RESULTS

The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015).

CONCLUSION

This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure A.A.H reports consulting fees from Merck Sharp & Dohme. H-C.H., R.D. and E.D. are employees of Decipher Biosciences. F.F. reports receiving fees for serving as a consultant from Janssen during the conduct of the study, Celgene, Blue Earth Diagnostics, Astellas, Myovant, Roivant, Genentech, and Bayer; being a co-founder having stock options in PFS Genomics; and having stock options and serving on the scientific advisory board of SerImmune Stock outside the submitted work. G.A. reports personal fees, research support and travel support from Janssen during the conduct of the study; personal fees and/or travel support from Astellas, Pfizer, Millennium Pharmaceuticals, Ipsen, Ventana, Veridex, Novartis, Abbott Laboratories, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Takeda and Sanofi-Aventis and research funding from AstraZeneca, Innocrin Pharma and Arno Therapeutics outside the submitted work; in addition, G.A.’s former employer, The Institute of Cancer Research (ICR), receives royalty income from abiraterone acetate and GA receives a share of this income through ICR’s Rewards to Discoverers scheme. E.M.V.A reports advisory/consulting role: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support: Novartis, BMS; equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; travel reimbursement: Roche/Genentech; patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation. P.T.T. reported receiving grants from RefleXion Medical, the Prostate Cancer Foundation, and Movember Foundation; personal fees from Noxopharm, Janssen-Taris Biomedical, Myovant, AstraZeneca, and RefleXion; grants from Astellas and Bayer Healthcare; and owning patent No. 9114158 (with royalties from Natsar Pharmaceuticals) outside the submitted work. D.E.S reports personal fees: Janssen, AstraZeneca, Bayer, Boston Scientific, and Blue Earth; funding: Janssen. G.L. is a co-founder and chief medical officer of AIQ Solutions (Madison, WI). M.A.A. reports past consultation for Pfizer, Astellas, and Exelixis, and current research funding from Arcus, Pfizer, and Merck. C.J.S. report consulting or advisory role: Sanofi, Janssen, Astellas Pharma, Bayer, Genentech, Pfizer, Lilly; research funding: Janssen Biotech (Inst), Astellas Pharma (Inst), Sanofi (Inst), Bayer (Inst), Sotio (Inst), Dendreon (Inst); patents, royalties, other intellectual property: Pathenolide (Indiana University): dimethylaminoparthenolide (Leuchemix); Exelixis: Abiraterone plus cabozantinib combination; stock or other ownership: Leuchemix.