ORLANDO, Fla.—The road to finding more effective therapy for prostate cancer—especially metastatic castration-resistant prostate cancer—is paved with disappointments, researchers reported in several studies here at the Genitourinary Cancers Symposium.
Despite hopeful early signs of effectiveness or preclinical encouragement, the following proved to be unsuccessful with more extensive research:
* Dasatinib: In the Phase III READY trial, median overall survival was 21.2 months among 760 men with castrate-resistant prostate cancer treated with docetaxel alone compared with 21.5 months among 762 men treated with both docetaxel and dasatinib (Abstract LBA8).
* Aflibercept: In the Phase III VENICE trial, which compared 612 patients with castration-resistant prostate cancer taking aflibercept plus docetaxel with 612 patients on placebo plus docetaxel, overall survival was 22.1 month with aflibercept and 21.2 months with placebo (Abstract 13).
* Cediranib: In the Phase II NCI7451 study, the 12-month median overall survival rate among 30 castrate-resistant prostate cancer patients treated with docetaxel, prednisone, and cediranib was 71 percent compared with 76 percent among 28 patients treated with docetaxel and prednisone (Abstract 38).
* Temsirolimus: In a Phase II study, the planned enrollment of 20 patients was halted prematurely after 11 men with castration-resistant prostate cancer were enrolled because it appeared that single-agent temsirolimus had no apparent efficacy (Abstract 105). Only one patient showed more than a 30 percent decline in prostate-specific antigen (PSA); progression-free survival was 1.9 months, and overall survival was 8.8 months.
* Linsitinib: In a Phase II study, men who did not yet require opioids to control pain from metastatic castration-resistant prostate cancer did not appear to have any meaningful clinical benefit from treatment with linsitinib, which targets the insulin-like growth factor-1 receptor (Abstract 197). Among the 17 patients in the study, transient decreases in PSA were observed in a small subset of patients.
* Zoledronic Acid: In the CALGB (Alliance) 90202 study, early treatment of bone metastases with zoledronic acid among men with castration-sensitive prostate cancer did not appear to increase overall survival or the time to skeletal-related events (Abstract 27). After a median of two years of follow-up, the time to a first skeletal event in the 323 men assigned to receive zoledronic acid was 32.5 months while the time to first skeletal event in the placebo patients was 29.8 months; overall survival in the two groups was also similar.
Ian Thompson, MD, Professor and Chair of Urology at the University of Texas at San Antonio, said that despite the various failures in these trials, the research community needs to continue:
“The concept that we just say it is too hard; that we are not going to push the envelope, is just unacceptable,” he said in an interview. “While this is a difficult disease to manage, we have made enormous progress.
“I am cautiously optimistic that one of these days we are going to be swinging at home plate and we are going to get beyond first base and that little white ball is going to go over the fence and we will have a treatment that will keep men disease-free for many years.”
One of the researchers who thought that home run could be delivered with dasatinib is John Araujo, MD, Assistant Professor of Genitourinary Cancer at the University of Texas MD Anderson Cancer Center. At his late-breaker poster presentation, he said that he and his research colleagues were confident that they had observed evidence in earlier clinical trials that by adding the kinase inhibitor to standard treatment there would be clinically meaningful improvements among the patients in the study.
But that didn't happen. “Many of us were surprised by these results because we thought we saw improvements in our patients, but the results showed no difference between the groups,” he said in an interview. Patients who received dasatinib in addition to standard docetaxel treatment did not show any statistical benefit compared with treatment with docetaxel alone.
Geralyn Trudel, PhD, Senior Director of Oncology Global Clinical Research for the drug's manufacturer, Bristol-Myers Squibb, noted that dasatinib might be tried again if scientists can identify a population that is likely to respond to dasatinib.
Treatment with another targeted agent, aflibercept, also failed to distinguish itself from placebo, and was associated with adverse side effects that let to early discontinuation of the drug, said Ian Tannock, MD, Professor of Medicine at the University of Toronto/Princess Margaret Hospital, in an interview at his poster study.
In addition to not observing a difference in overall survival, the study also showed little difference between aflibercept and placebo in progression-free survival—a median of 6.9 months in the patients receiving aflibercept and a median of 6.2 months for those receiving docetaxel alone.
The time to skeletal-related events was a median of 15.3 months with aflibercept and 15.0 months with placebo. About 69 percent of patients in the aflibercept group showed a PSA response compared with 63.5 percent of those in the placebo group. About 38 percent of men receiving aflibercept achieved a tumor response compared with 28 percent of the placebo patients.
Regarding tolerability, about 35 percent of the patients on aflibercept were able to tolerate 10 or more infusions compared with 49 percent of the patients in the placebo group.
The researchers using cediranib to treat metastatic castrate-resistant prostate cancer were unable to see any difference between the tyrosine kinase inhibitor used in combination with docetaxel or use of docetaxel alone.
“The six-month and 12-month progression-free survival rate was comparable in both arms,” reported Elisabeth Heath, MD, Assistant Professor of Oncology at Wayne State University. There were also no meaningful differences in the six- and 12-month overall survival times.
The researchers also noted that adverse events, particularly Grade 4 neutropenia, were observed with cediranib. Reductions of the dose of cediranib helped patients tolerate the drug, she noted.
Recruitment of patients in this trial was halted because of lack of efficacy and feasibility, reported Andrew Armstrong, MD, Associate Professor of Surgery and of Medicine at Duke University School of Medicine.
He and his colleagues did observe a median reduction of 48 percent in circulating tumor cells, but most of the men still had unfavorable levels of the biomarker. “Future studies should focus on combination approaches or novel PI3K [phosphatidylinositide 3-kinase] pathway inhibitors,” Armstrong said.
While the initial study of linsitinib did not find meaningful activity in the 18 patients treated, Jorge Garcia, MD, Assistant Professor of Medicine at the Cleveland Clinic, suggested that there could still be a role for the agent.
“Development of castrate-resistant prostate cancer is a complex biologic process that involves the androgen receptor signaling pathway,” he said at his poster presentation. “There is biologic rationale for the combination of linsitinib with an androgen-receptor inhibitor.”
The zoledronic acid study aimed at preventing skeletal events and improving survival was terminated prematurely after 284 events (60% of the total of 470 events) had been experienced by the 645 patients in the study, reported Matthew Smith, MD, PhD, Associate Professor of Medicine at Massachusetts General Hospital/Harvard Medical School.
The trial was funded by the National Cancer Institute and Novartis Oncology. The withdrawal of the drug by the company terminated the trial, and limited the study's statistical power, the researchers said. However, little differences in outcomes were observed after 36 months.
More News from the GU Symposium in the Special Edition supplement to this issue – access it under “Archives”
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