Genetic Biomarker Test Predicts How Men With High-Risk Prostate Cancer Will Respond to RT, Hormone Therapy

A new meta-analysis finds that a genetic biomarker test accurately predicts how men with high-risk prostate cancer will respond to treatment with radiation and hormone therapy. The study, which examined biopsy samples collected from three large, randomized clinical trials, indicates that physicians potentially can use genetic test scores to personalize treatment for men with the most aggressive form of prostate cancer. Findings were presented October 25 at the American Society for Radiation Oncology (ASTRO) Annual Meeting in Chicago.

Two-thirds of prostate cancer deaths occur in patients with high-risk prostate cancer, for whom standard treatment involves radiation therapy and two years of hormone therapy. Balancing survival risk with quality of life is an important consideration for many men with this disease. Hormone therapy can cause difficult side effects, including hot flashes, loss of libido and possible cardiovascular and cognitive changes. Researchers believe that biomarkers could potentially be used to develop more precise treatment guidelines and designate who might benefit from less therapy or who might benefit from additional treatment with newer hormonal agents.

"When a man is diagnosed with high-risk prostate cancer, we don't have a widely accepted way to sub-classify their cancer and truly personalize their therapy, but we think we will in the near future," said lead author Paul L. Nguyen, MD, a professor at Harvard Medical School and vice chair for clinical research in the department of radiation oncology at Brigham and Women's Hospital/Dana-Farber Cancer Institute in Boston.

Dr. Nguyen and his team utilized the Decipher biopsy test, which analyzes the activity of 22 genes in prostate tumors to produce a score reflecting how aggressive a patient's cancer is. "We are optimistic that this score can tell us which men should have their treatment de-intensified, meaning they will get less hormone therapy, and which men should have their therapy intensified, meaning they will get an additional, second-generation hormone therapy," said Dr. Nguyen. "With this genetic marker, we hope to personalize therapy for men with high-risk prostate cancer rather than having a one-size-fits-all approach."

Researchers calculated Decipher scores using RNA extracted from archival biopsy samples collected in three major prostate cancer trials (RTOG-9202, n=90; RTOG-9413, n=172; RTOG-9902, n=123). Then, they examined how closely these Decipher scores were associated with long-term outcomes.

The genetic signature predicted which patients were more likely to develop distant metastases (HR 1.24, 95% CI 1.11-1.39), which were more likely to die of their prostate cancer (HR 1.27, 95% CI 1.13-1.43) and which were more likely to die from any cause (HR 1.12, 95% CI 1.05-1.20). For example, the rate of distant cancer metastasis at 10 years was 29% for patients whose scores indicated they had more aggressive cancer, compared to 13% for those whose scores signaled lower risk.

While the Decipher test was previously validated using tissue samples taken after radical prostatectomy, the current meta-analysis examined tissue taken before treatment, at the time of initial diagnosis. "This study is the first to validate a genetic biomarker for high-risk prostate cancer using pre-treatment archival tissue from large prospective randomized trials," said Dr. Nguyen. "Using archival tissue samples from a wide range of centers and patients—hundreds of cancer centers across the country—shows that this test can be helpful for many men with high-risk disease."

The age of the samples also meant that researchers could examine very long-term outcomes on the patients with high-risk prostate tumors. "A strength of using this tissue is that we have the complete follow-up for 20 to 30 years on these patients," said Dr. Nguyen.

Dr. Nguyen emphasized that the test needs further validation before it can become widely adopted. To that end, the NRG-GU009/PREDICT-RT trial led by Dr. Nguyen and Dr. Oliver Sartor is currently enrolling patients with high-risk prostate cancer to test Decipher's predictive validity in a prospective randomized trial.

"For a man with high-risk prostate cancer, this genetic score can be a very powerful prognostic tool that can tell us whether he is likely to be cured from treatment or is likely to see his cancer return again," said Dr. Nguyen. "I see this as a great opportunity to change the standard of care for patients in the future by using genomics to personalize therapy."

Abstract 95, American Society for Radiation Oncology (ASTRO) 2021 Annual Meeting

Validation of a 22-gene Genomic Classifier in the NRG Oncology/RTOG 9202, 9413 and 9902 Phase III Randomized Trials: A Biopsy-Based Individual Patient Meta-Analysis in High-Risk Prostate Cancer

1. L. Nguyen1, H. C. Huang2, E. Davicioni3, H. M. Sandler4, W. U. Shipley5, J. A. Efstathiou6, J. Simko7, A. Pollack8, A. P. Dicker9, M. Roach III10, S. A. Rosenthal11, M. Morginstin12, L. Mendez13, A. C. Hartford14, W. A. Hall15, A. B. Desai16, R. Rabinovitch17, C. A. Peters18, J. Rodgers19, and F. Y. Feng20; 1Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, 2Decipher Biosciences, San Diego, CA, United States, 3GenomeDx Inc., San Diego, CA, 4Cedars-Sinai Medical Center, Los Angeles, CA, 5Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 6Harvard Medical School, Boston, MA, 7University of California, San Francisco, San Francisco, CA, 8Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL, 9Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, 10University of California San Francisco, Department of Radiation Oncology, San Francisco, CA, 11Sutter Medical Group and Cancer Center, Sacramento, CA, 12Einstein Medical Center, Philadelphia, PA, 13Department of Oncology, Division of Radiation Oncology, London Health Sciences Centre, Western University, London, ON, Canada, 14Department of Medicine, Radiation Oncology, Dartmouth-Hitchcock Medical Center / Norris Cotton Cancer Center, Lebanon, NH, 15Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, 16Summa Physicians Inc., Akron, OH, 17University of Colorado, Denver, CO, 18Northeast Radiation Oncology Center, Dunmore, PA, 19NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 20Department of Radiation Oncology, University of California San Francisco, San Francisco, CA

Purpose/Objective(s): Decipher is a prognostic 22-gene genomic classifier (GC) prospectively validated post-prostatectomy. Herein, we validate the performance of the GC in pre-treatment biopsy samples within the context of three randomized phase III high-risk definitive radiotherapy trials.

Materials/Methods: Following a pre-specified and approved CTEP-CCSC analysis plan (NRG-GU-TS006), we obtained all available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on NRG/RTOG 9202, 9413, and 9902 phase III randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability of GC for distant metastases (DM), and secondary was prostate cancer-specific mortality (PCSM) and overall survival (OS), with Cox multivariable analyses (MVA).

Results: GC scores were obtained on 385 samples (n=90 on 9202, n=172 on 9413, and n=123 on 9902), of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9, 13). On MVA, the GC (per 0.1 unit) was independently associated with DM (HR 1.24, 95%CI 1.11-1.39), PCSM (HR 1.27, 95%CI 1.13-1.43), and OS (HR 1.12, 95%CI 1.05-1.20) after adjusting for age, PSA, Gleason score, cT-stage, trial, and randomized treatment arm. For categorical GC, on MVA, GC score ≥ 0.45 (representing the intermediate and high GC categories) had worse DM (HR 2.18, 95%CI 1.25-3.80), PCSM (HR 2.34, 95%CI 1.31-4.16), and OS (HR 1.45, 95%CI 1.03-2.04) outcomes as compared to those with low GC. Cumulative incidence of distant-metastasis at 10-years was 29% (95% CI 20-38%) for intermediate/high GC vs 13% (95% CI 7-18%) for low GC. For the subset with GC>0.85, the threshold for inclusion in the intensification study of NRG GU009 (PREDICT-RT), at 5-years and 10-years DM was 29% (95% CI 7-52%) and 41% (95% CI 17-66%). GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy (ADT).

Conclusion: This is the first validation of any gene expression biomarker on pre-treatment biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT (NCT04513717) will further determine the optimal therapy based on GC score.

Author Disclosure: P.L. Nguyen: Research Grant; Janssen, Astellas, Bayer. Honoraria; Bayer, Janssen. Consultant; Infinity Pharmaceuticals, GI Windows, Astellas, Augmenix, Boston scientific, COTA, Myovant. Advisory Board; Ferring, Medivation, Dendreon, Astellas, Bayer, Blue Earth. Stock Options; Augmenix. ; Genitourinary Cancers Symposium. H. Huang: None. E. Davicioni: Stock; Decipher Biosciences. ; Decipher Biosciences. H.M. Sandler: Consultant; Janssen, Caribou Publishing. Stock; Advanced Medical Isotope Corporation. W.U. Shipley: None. J.A. Efstathiou: None. J. Simko: None. A. Pollack: None. A.P. Dicker: Research Grant; Radiation Therapy Oncology Group. Consultant; Wilson Socini, European Commission. Advisory Board; EMD Serono, Roche, Janssen, Oranomed. Travel Expenses; Prostate Cancer Foundation. ; Department of Defense. M. Roach: Honoraria; Blue Earth, Myriad, Noxopharma. Consultant; Janssen Pharma, International Atomic Energy Agency. Speaker's Bureau; Accuray. Advisory Board; Janssen Pharma, Bayer, Blue Earth, Myriad, Genomic Health, Noxopharma. Travel Expenses; Janssen Pharma, International Atomic Energy Agency, Bayer, Blue Earth, Myriad, Noxopharma. Stock; Abbot. S.A. Rosenthal: None. M. Morginstin: None. L. Mendez: None. A.C. Hartford: As secretary I serve on the governing body of CARROS. I serve to support the organization of records and management of the group. CARROS has a close working relationship with ASTRO, particularly in the functioning of radiation oncologists within the ACR; CARROS. W.A. Hall: Research Grant; Elekta, National Cancer Institute, American Cancer Society. A.B. Desai: None. R. Rabinovitch: None. C.A. Peters: None. J. Rodgers: None. F.Y. Feng: Consultant; Genentech, Roivant. Advisory Board; Janssen, Astellas, Bayer, Blue Earth Diagnostics, Celgene, Myovant, SerImmune. ; PFS Genomics. Oversee clinical trials in GU cancers in this cooperative group; NRG Oncology Group.