AACR 2015: Subgroup of Men With Metastatic Prostate Cancer Respond to Olaparib Treatment
Men with metastatic, castration-resistant prostate cancer who had mutations in genes linked to repair of damaged DNA were significantly more likely to respond to treatment with olaparib (Lynparza) compared with patients who had the disease without these mutations. These findings from the first stage of the phase II TOPARP clinical trial were presented at the AACR Annual Meeting 2015, held April 18 to 22 in Philadelphia (Abstract CT322).
Study Details
Joaquin Mateo, MD, a Clinical Research Fellow in the Prostate Targeted Therapy Group and Drug Development Unit at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in the United Kingdom, and colleagues enrolled 50 men with metastatic, castration-resistant prostate cancer in TOPARP-A. Among the 49 patients for whom there were evaluable data, 16 had a response to olaparib treatment; 6 had radiologic responses, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1; and 11 patients had biochemical responses, as assessed by a greater than 50% decrease in prostate-specific antigen (PSA) levels. Four of these responses lasted more than 1 year.
Next-generation sequencing detected mutations in genes associated with DNA repair in tumor samples from 15 of the 49 patients evaluated. Of these patients, 13 had a response to olaparib.
The researchers calculated the specificity of the DNA-repair gene panel to be 94%. According to Dr. Mateo, this means that 94% of patients without these mutations will be correctly identified as not having the mutations. This will help clinicians select the right treatment for a patient, as they can be reasonably certain that olaparib will not benefit a patient testing negative for the mutations.
Next Steps in TOPARP Trial
“TOPARP is an investigator-initiated clinical trial designed to test the anticancer effect of the PARP [poly ADP-ribose polymerase] inhibitor olaparib in men with metastatic, castration-resistant prostate cancer and, at the same time, to identify biomarkers predictive of response to olaparib,” said Dr. Mateo.
“The data from TOPARP-A show that single-agent PARP inhibition with olaparib has durable antitumor activity in men with metastatic, castration-resistant prostate cancer and identifies a molecularly distinct subgroup of patients that responds to the drug,” added Dr. Mateo, who is also a doctoral candidate in the laboratory of Johann S. de Bono, MD, PhD, Professor of Experimental Cancer Medicine at The Institute of Cancer Research.
“These are potentially the first clinical data supporting molecular stratification of treatment in prostate cancer, and we are testing this idea in the second stage of the TOPARP trial, TOPARP-B,” continued Dr. Mateo. “For TOPARP-B, we are enrolling only patients who screen positive for the DNA-repair mutations linked to response in TOPARP-A.”
This study was supported by the Cancer Research U.K. Clinical Trials Awards and Advisory Committee, SU2C, PCF, the Experimental Cancer Medicine Center, and the U.K. National Institute for Health Research Biomedical Research Center.
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