Targeting Metastatic Prostate Cancer

Men with metastatic, castrate-resistant prostate cancer with mutations in genes linked to DNA repair responded to targeted therapy.

Data from the first stage of a Phase II Trial of Olaparib in Patients with Advanced Castration Resistant Prostate Cancer (TOPARP), suggests men with metastatic, castration-resistant prostate cancer that had mutations in genes linked to repair of damaged DNA were significantly more likely to respond to treatment compared with those who did not have the mutations in their tumors.

The data from the trial were presented at the American Association for Cancer Research (AACR) Annual Meeting 2015.

"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 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.

"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 identify a molecularly distinct subgroup of patients that respond to the drug," added Dr. Mateo, who is also a doctoral candidate in the laboratory of Johann S. de Bono, MBBS, PhD, professor of experimental cancer medicine at The Institute of Cancer Research.

Prostate cancer is projected to be the most commonly diagnosed cancer among men in the United States.

In 2015 an estimated 220,800 men in the United States are expected to be diagnosed with prostate cancer and some 27,530 are expected to die of the disease, according to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program.

"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," said Dr. Mateo. "For TOPARP-B, we are enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP-A."

Dr. Mateo and his 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: Six patients had radiological 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 percent decrease in prostate-specific antigen (PSA) levels. Four of these responses lasted more than one 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 percent.

According to Dr. Mateo, this means that 94 percent of patients without these mutations will be correctly identified as not having the mutations and this will help clinicians select the right treatment for a patient because they can be reasonably certain that olaparib will not benefit a patient testing negative for the mutations.

Learn more about this study here.​

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