Nick Mulcahy

April 22, 2015

PHILADELPHIA — The bevy of prostate cancer treatments approved for the treatment of metastatic disease in the past few years have had, in addition to acceptable efficacy and toxicity, another commonality: none require the molecular testing that helps select patients for treatment.

This is increasingly an oddity in the era of "precision" oncology, when such testing identifies patients more likely to respond to a targeted drug.

But change could be on the way, suggests research presented here at the American Association for Cancer Research (AACR) 2015 Annual Meeting.

In a phase 1B trial from the United Kingdom, men with heavily pretreated metastatic castration-resistant prostate cancer who had certain gene mutations were much more likely to respond to treatment with the oral drug olaparib (Lynparza, AstraZeneca) than men with the disease but without the mutations, lead author Joaquin Mateo, MD, a fellow at the Institute of Cancer Research in London, said during a press briefing at the meeting.

Of the 49 patients in the TOPARP-A trial, 16 had a response to olaparib (response rate, 32.7%, 95% confidence interval [CI], 20.0 - 47.5). The response rate was the primary end point of the study. Four of the these men responded for more than 1 year, which is "quite a big achievement for a later-stage population," said Dr Mateo.

The study had a second major objective: to identify the molecular signature for sensitivity to olaparib. To that end, the investigators employed next-generation sequencing that detected mutations associated with DNA repair in tumor samples.

The genomic testing of the tumor tissues identified a set of the most prominently associated genetic mutations and deletions; 15 of the 49 men were deemed to be "biomarker positive" because of the status of these mutations and deletions. Of these 15 men, 13 had responded to olaparib (86.7%).

In other words, if a patient was a responder, chances were very high that he was biomarker positive.

The specificity of the gene panel used in the study was 94%.

"We hope that this is a step toward the molecular stratification of treatment for prostate cancer," said Dr Mateo.

However, he explained that the current trial is not a validation study of the biomarker panel. That is the next item on their research agenda for olaparib and prostate cancer, and is referred to as TOPARP-B.

Tumors lacking BRCA function are sensitive to PARP inhibition.

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

Olaparib is a PARP inhibitor approved for use in the United States for the treatment of ovarian cancer, but only in women with BRCA mutations.

"Tumors lacking BRCA function are sensitive to PARP inhibition," said Dr Mateo.

Prostate cancers are associated with a set of genetic mutations, including BRCA2, ATM, and CHEK2, all of which are sensitive to PARP inhibitors, he explained. The biomarker suite used in this study included these mutations and a host of others.

Dr Mateo provided some context for the frequency of these mutations. Other research presented at the AACR meeting this year, he said, indicates that BRCA2 is present in about 12% of prostate cancers and ATM is present in about 7%. They are the most common of the various genetic mutations associated with prostate cancer.

New therapies for metastatic castration-resistant prostate cancer are needed, said William Nelson, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

"Our basic hormonal therapies for prostate cancer have been around for 70 years," he pointed out. The more recent treatments, such abiraterone and enzalutamide, target the androgen receptor and have given clinicians "more mileage" in treatment. But no approach, including chemotherapy, is curative, he said, so the "next question" becomes, "What else are we going to need to target?"

This study addresses that question, suggested Dr Nelson.

Response to treatment in the study was defined as a radiologic response (n = 6), assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, and biochemical response was defined as a decrease of more than 50% in prostate-specific antigen (PSA) level (n = 10).

For the men in this study, average age was 67.5 years, performance status ranged from 0 to 2 (80% were either 0 or 1), and the average duration of castration-resistant prostate cancer was 2.2 years.

Mean baseline PSA was very high (349.5 µg/L). All of the men had received previous chemotherapy, and 96% had received abiraterone. In addition, about one-quarter had received enzalutamide and about one-quarter had been treated with radiotherapy.

The study was supported by funds from the Cancer Research UK Clinical Trials Awards and Advisory Committee, SU2C, PCF, the Experimental Cancer Medicine Center, and the UK National Institute for Health Research Biomedical Research Center. Dr Mateo has disclosed no relevant financial relationships. Senior author Johann de Bono, MD, from The Institute of Cancer Research and The Royal Marsden in Sutton, United Kingdom, reports financial ties to AstraZeneca.

American Association for Cancer Research (AACR) 2015 Annual Meeting: Abstract 8311. Presented April 21, 2015.


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