Abstract
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. 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. 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). 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.
Highlights
Most men with metastatic hormone-sensitive prostate cancer respond to testosterone suppression, commonly referred to as androgen-deprivation therapy (ADT), achieved by medical or surgical castration; Volume 32 - Issue 9 - 2021 the durability of response and time to castration resistance are variable
A significant overall survival (OS) improvement favoring ADT þ D was observed in the analytic cohort [median OS 53.9 versus 32.4 months; hazard ratio (HR) 0.58, 95% confidence intervals (CIs) 0.380.87; P 1⁄4 0.009]
We demonstrate that comprehensive gene expression profiling of primary prostate tumors obtained prior to ADT in men with metastatic hormone-sensitive prostate cancer (mHSPC) has the potential to prognosticate outcomes on ADT alone and predict benefit from chemohormonal therapy
Summary
Most men with metastatic hormone-sensitive prostate cancer (mHSPC) respond to testosterone suppression, commonly referred to as androgen-deprivation therapy (ADT), achieved by medical or surgical castration; Volume 32 - Issue 9 - 2021 the durability of response and time to castration resistance are variable. 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 (ARA), and high Decipher risk disease.
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