Alliance trial reveals gene variant may affect prostate cancer drug efficacy

Data from a major U.S. clinical trial from the Alliance for Clinical Trials in Oncology has uncovered a genetic factor that may inform how to optimize the dosing of abiraterone, a widely used hormone treatment for advanced prostate cancer. Published in Clinical and Translational Science, this secondary analysis of Alliance A032201 could lead to more personalized treatments for patients.

“This study is the first to show how an individual’s genetics can impact how abiraterone is metabolized. These findings could lead to optimized dosing strategies in the future, rather than giving the same dose of the drug to everyone, as we do now,” said author Michael Morris, MD, the Steven A. Greenberg Chair in Prostate Cancer Research at Memorial Sloan Kettering Cancer Center in New York.

The Alliance A031201 trial was a large phase III study conducted by the Alliance, a national research network supported by the National Cancer Institute. The trial enrolled 1,311 men with metastatic castration-resistant prostate cancer and randomized them to enzalutamide, another hormonal therapy, either alone or with abiraterone.

As part of this study, researchers collected genetic data and measured drug levels in the blood to see if certain genes influence how these medications are metabolized. That genomic data was analyzed for this current research.

“We discovered that men who carry a specific version of the gene SULT2A1 clear abiraterone from their bodies more slowly,” said lead author Nadine Norton, PhD, Associate Professor of Cancer Biology for the Mayo Clinic in Jacksonville, FL. “This means the drug stays in the system longer, which could affect how well it works and whether side effects occur.”

Interestingly, the study did not find any similar genetic effect for enzalutamide, suggesting that this discovery is unique to abiraterone. This finding opens the door to more personalized care. In the future, doctors may be able to test for this gene variant (found in about 15% of people of European descent) and adjust abiraterone doses to make treatment safer and more effective.

“The initial trial gave us the data to make this discovery,” added Dr. Morris, who was study chair of the original Alliance study. “This new genetic finding is an important step toward precision medicine in prostate cancer care.”

In addition to Drs. Morris and Norton, investigators for this current research included scientists from Dartmouth University, Johns Hopkins University, Memorial Sloan Kettering Cancer Center, The Ohio State University, University of Chicago, University of Maryland, University of Michigan and the National Institutes of Biomedical Innovation in Osaka, Japan.

This research was supported by the grants from National Cancer Institute, Astellas Pharma Inc., and Pfizer. 

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References: Alliance A031201; Phase III Trial of Enzalutamide (NSC #766085) Versus Enzalutamide, Abiraterone and Prednisone for Castration Resistant Metastatic Prostate Cancer

Clinical and Translational Science: Association of SULT2A1 Locus With Abiraterone Clearance in the Alliance A031201: Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer; https://doi.org/10.1111/cts.70425

The Alliance for Clinical Trials in Oncology is a national leader in advancing cancer research, uniting more than 25,000 cancer specialists at 115 main institutions and 1,400 affiliates across the U.S. and Canada. As part of the National Clinical Trials Network and a leading research base for the NCI Community Oncology Research Program, the Alliance conducts pioneering, practice-changing clinical trials that improve outcomes and reshape standards of care. Its work has led to multiple FDA approvals, influenced national guidelines, and produced hundreds of high-impact publications. More than 40,000 participants have taken part in Alliance studies, and its growing biospecimen repository now includes more than 1.5 million samples, collected over the past 30 years. Learn more at www.AllianceforClinicalTrialsinOncology.org.