Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2021 Jul 1;7(7):1005-1014.
doi: 10.1001/jamaoncol.2021.1463.

Association of Molecular Subtypes With Differential Outcome to Apalutamide Treatment in Nonmetastatic Castration-Resistant Prostate Cancer

Felix Y Feng  1 , Shibu Thomas  2 , Fred Saad  3 , Michael Gormley  2 , Margaret K Yu  4 , Deborah S Ricci  2 , Brendan Rooney  5 , Sabine Brookman-May  4 , Sharon McCarthy  6 , David Olmos  7   8 , Simon Chowdhury  9 , Boris Hadaschik  10   11 , Yang Liu  12 , Elai Davicioni  12 , Matthew R Smith  13   14 , Eric J Small  1
Affiliations
Randomized Controlled Trial

Association of Molecular Subtypes With Differential Outcome to Apalutamide Treatment in Nonmetastatic Castration-Resistant Prostate Cancer

Felix Y Feng et al. JAMA Oncol. .

Abstract

Importance: There is a need to identify prognostic biomarkers to guide treatment intensification in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Objective: To examine whether molecular subtypes predict response to apalutamide, using archived primary tumor samples from the randomized, double-blind, phase 3 SPARTAN trial.

Design, setting, and participants: In this cohort study, gene expression data from 233 archived samples from patients with nmCRPC enrolled in the SPARTAN trial were generated using a human exon microarray. The present analysis was conducted from May 10, 2018, to October 15, 2020.

Interventions: Patients were randomized (2:1) to apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) or placebo+ADT.

Main outcomes and measures: Patients were stratified into high-risk and low-risk categories for developing metastases based on genomic classifier (GC) scores for high (GC >0.6) and low to average (GC≤0.6) and into basal and luminal subtypes; associations between these molecular subtypes and metastasis-free survival (MFS), overall survival (OS), and progression-free survival 2 (PFS2) were evaluated using Cox proportional hazards regression and Kaplan-Meier analysis.

Results: Median age of the 233 included patients was 73 (range, 49-91) years. A total of 116 of 233 patients (50%) in the SPARTAN biomarker subset had high GC scores. Although all patients receiving apalutamide+ADT had improved outcomes, having high GC scores was associated with the greatest improvement in MFS (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P < .001), OS (HR, 0.52; 95% CI, 0.29-0.94; P = .03), and PFS2 (HR, 0.39; 95% CI, 0.23-0.67; P = .001) vs placebo+ADT. In total, 152 of 233 patients (65%) had the basal molecular subtype. Although there were no significant differences in MFS, PFS2, or OS between patients with the luminal vs basal subtype in the placebo+ADT arm, patients with the luminal subtype in the apalutamide+ADT arm had a significantly longer MFS (apalutamide+ADT: HR, 0.40; 95% CI, 0.18-0.91; P = .03; placebo+ADT: HR, 0.66; 95% CI, 0.33-1.31; P = .23) compared with patients with basal subtype; similar trends were observed for OS (apalutamide+ADT: HR, 0.50; 95% CI, 0.25-0.98; P = .04; placebo+ADT: HR, 0.78; 95% CI, 0.38-1.60; P = .50), and PFS2 (apalutamide+ADT: HR, 0.71; 95% CI, 0.42-1.22; P = .22; placebo+ADT: HR, 0.72; 95% CI, 0.38-1.39; P = .33). In regression analysis, the luminal-basal subtype score was significantly associated with MFS in patients receiving apalutamide+ADT (HR, 2.65; 95% CI, 1.15-6.08; P = .02), whereas GC score was significantly associated with MFS in placebo+ADT recipients (HR, 2.09; 95% CI, 1.02-4.27; P = .04).

Conclusions and relevance: The findings of this study suggest that the GC score and basal-luminal subtype derived from archived tumor specimens may be biomarkers of response to apalutamide+ADT in the nmCRPC setting. Although overall, the addition of apalutamide to ADT was beneficial, higher-risk and luminal subtypes appeared to benefit most. Obtaining GC scores may be useful for identifying patients for early treatment intensification with apalutamide, and basal-luminal subtyping may be a beneficial approach for patient selection for further treatment intensification in trials combining novel therapies with apalutamide.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Feng reported 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. Dr Thomas reported a patent for Janssen R&D pending. Dr Saad reported receiving grants, personal fees, and nonfinancial support from Janssen during the conduct of the study; grants and personal fees from Astellas, and grants and personal fees from Bayer outside the submitted work. Drs Yu, Rooney, Brookman-May and McCarthy are Janssen employees. Dr Olmos reported receiving grants from Programa Ramón y Cajal, Ministerio de Ciencia, Gobierno de España his salary, including all research activities, personal fees from Janssen paid to the institution, and nonfinancial support from Janssen for travel during the conduct of the study; grants and personal fees from AstraZeneca paid to the institution, nonfinancial travel support from AstraZeneca, serving as an unpaid member of the AstraZeneca trial steering committee, grants and personal fees from Bayer paid to the institution, nonfinancial support from Bayer for travel; serving as serving as an unpaid member of the Bayer trial steering committee fees from Clovis and Daiichi Sankyo for serving as a member of the advisory board, nonfinancial travel support from F. Hoffman-La Roche for travel, serving as a member of the steering committee for a Genentech trial, nonfinancial support from Genentech for travel, and personal fees from MSD for serving as a member of the advisory board outside the submitted work. Dr Chowdhury reported receiving personal fees from Janssen, Astellas, Bayer, AstraZeneca, Novartis, Clovis, and BeiGene, and held stock in Curve.life during the conduct of the study. Dr Hadaschik reported receiving personal fees from Astellas Pharma, Bayer, Bristol-Myers Squibb, Janssen, Lightpoint Medical, ABX, AstraZeneca, and Pfizer, and nonfinancial support from Janssen outside the submitted work. Dr Liu is an employee of Decipher Biosciences. Dr Davicioni is an employee of Decipher Biosciences; in addition, Dr Davicioni had a patent for US10865452B2 pending for Decipher Biosciences. Dr Smith reported receiving consulting fees from Janssen, Bayer, and Pfizer outside the submitted work. Dr Small reported owing stock in Fortis Therapeutics and Harpoon Therapeutics, and receiving personal fees from Janssen, Johnson & Johnson, Teon Therapeutics, Ultragenyx, BeiGene, and Tolero outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Distribution of Decipher and Basal-Luminal Scores in the SPARTAN Study and the Decipher Genomic Resource Informatics Database (GRID)
A, Expression of genes in patients with high (>0.6) and low (≤0.6) genomic classifier (GC) scores and luminal and basal tumors. B, Proportion of patients with basal and luminal tumors. C, High-risk and lower-risk GC scores in the SPARTAN biomarker subset and the Decipher GRID database from patients treated with radical prostatectomy (RP). nmCRPC indicates nonmetastatic castration-resistant prostate cancer.
Figure 2.
Figure 2.. Associations of Decipher Risk Scores With Metastasis-Free Survival (MFS)
A, MFS by treatment arm in patients with high (>0.6) Decipher genomic classifier (GC) scores (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P < .001). B, MFS by treatment arm in patients with low (≤0.6) GC scores (HR, 0.46; 95% CI, 0.23-0.95; P = .04). C, MFS in patients with high and low GC scores in the group receiving apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) (HR, 1.11; 95% CI, 0.58-2.13; P = .75). D, MFS in patients with high and low GC scores within the placebo+ADT group (HR, 0.43; 95% CI, 0.22-0.85; P = .01). NR indicates not reached.
Figure 3.
Figure 3.. Associations of Basal and Luminal Subtypes With Metastasis-Free Survival (MFS)
A, MFS by treatment arm in patients with basal tumors (hazard ratio [HR], 0.34 (95% CI, 0.20-0.58; P < .001). B, MFS by treatment arm in patients with luminal tumors (HR, 0.22; 95% CI, 0.08-0.56; P = .002). C, MFS in patients with basal and luminal tumors within the group receiving apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) (HR, 0.40; 95% CI, 0.18-0.91; P = .03). D, MFS in patients with basal and luminal tumors within the placebo+ADT group (HR, 0.66; 95% CI, 0.33-1.31; P = .23). NR indicates not reached.
See this image and copyright information in PMC

Comment in

References

    1. Smith MR, Kabbinavar F, Saad F, et al. . Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23(13):2918-2925. doi:10.1200/JCO.2005.01.529 - DOI - PubMed
    1. Beer TM, Armstrong AJ, Rathkopf DE, et al. ; PREVAIL Investigators . Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433. doi:10.1056/NEJMoa1405095 - DOI - PMC - PubMed
    1. Ryan CJ, Smith MR, de Bono JS, et al. ; COU-AA-302 Investigators . Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148. doi:10.1056/NEJMoa1209096 - DOI - PMC - PubMed
    1. Smith MR, Saad F, Chowdhury S, et al. ; SPARTAN Investigators . Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546 - DOI - PubMed
    1. Small EJ, Saad F, Chowdhury S, et al. . Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019;30(11):1813-1820. doi:10.1093/annonc/mdz397 - DOI - PMC - PubMed

Publication types