ASCO GU: In Two Trials, Targeted Therapies Miss Mark for Prostate Cancer

February 16, 2013

In two phase III studies-READY and VENICE-targeted agents combined with standard first-line chemotherapy failed to increase overall survival for men with metastatic castration-resistant prostate cancer.

ORLANDO, Fla.-Researchers here at the 2013 Genitourinary Cancers Symposium presented the results of two negative phase III studies-READY and VENICE-of targeted agents that failed to increase overall survival  when combined with standard first-line chemotherapy docetaxel/prednisone for the treatment of men with metastatic castration-resistant prostate cancer.

Chemical structure of dasatinib

The two agents, aflibercept and dasatinib, both have different mechanisms of action and both had preclinical data to support use in a phase III trial; however, they are now both among a growing list of targeted agents that researchers have unsuccessfully tried to combine with standard treatment to improve survival for men with this disease.

“This is a tried and true approach in oncology. We take existing effective agents and try to add more,” said William Oh, MD, chief of the division of hematology and medical oncology at the Mount Sinai Hospital, during his discussion of the two trials. “Unfortunately, targeting VEGF and SRC [kinases] failed to improve survival with chemotherapy.”

A result that Oh said should prompt oncologists to question if these new drugs should have single-agent efficacy in prostate cancer, and whether or not existing preclinical models and early phase trials need improved designs to prevent the failure of many of the large phase III trials that are seen today.

READY

The results of the READY trial were presented by John C. Araujo, MD, depart of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center. READY tested the use of dasatinib in combination with docetaxel/prednisone vs docetaxel/prednisone alone in 1,522 patients with metastatic castration-resistant prostate cancer with progressive disease. Dasatinib is a tyrosine kinase inhibitor that inhibits the SRC kinase.

According to Araujo, preclinical trials of dasatinib indicated that the drug inhibited osteoclast function in the tumor microenvironment, and, in combination with docetaxel/prednisone, it was well tolerated and showed antitumor activity as indicated by PSA decline and partial tumor response.

However, results of the phase III trial showed that dasatinib did not improve overall survival compared with standard care. The overall survival for dasatinib was 21.5 months compared with 21.2 months for patients given placebo.

“Subgroups analyses indicated no advantage of dasatinib over the entire population in any of the subgroups analyzed,” Araujo said. “There were also no meaningful changes between the two arms in regard to response rates for urinary N-telopeptide, progression-free survival, or pain reduction.”

VENICE

The results of the VENICE trial were presented by Ian Tannock, MD, PhD, of Princess Margaret Hospital and the University of Toronto. The trial enrolled 1,224 patients. All patients were randomly assigned treatment with docetaxel/prednisone with or without aflibercept. Aflibercept is a recombinant human fusion protein that inhibits angiogenesis by binding VEGF-A, VEGF-B, and placental growth factor.

At a median follow-up of 3 years there was no difference between the arms for the primary endpoint of overall survival, or the secondary endpoint of progression-free survival. Median overall survival was 22.1 months in the aflibercept group vs 21.2 months in the placebo group.

When looking at some of the secondary response endpoints, patients assigned aflibercept had a slightly greater rate of prostate-specific antigen (PSA) response and tumor response, but these were not tested for significance because of a lack of significance on the primary endpoint, Tannock said.

In addition, patients assigned aflibercept had a higher rate of grade 3/4 adverse events compared with patients assigned placebo (76.9% vs 48.5%) , including a higher rate of fatal adverse events.