January 28, 2014—In a presscast held in advance of the 2014 Genitourinary Cancers Symposium (Jan. 30-Feb 1) in San Francisco, researchers reported survival improvements in genitourinary tumor types, indicating that some aspects of clinical practice could change as a result of the studies.
Enzalutamide Offers Overall Survival Benefit Prior to Chemo
In the phase III PREVAIL study, enzalutamide significantly reduced the risk of death, significantly delayed progression, produced meaningful responses in soft tissue disease, significantly delayed the time to initiating chemotherapy, and was well tolerated over an extended period of time in men with castration-resistant metastatic prostate cancer (mCRP) that progressed on androgen-deprivation therapy, according to Tomasz Beer, MD, Professor of Medicine and Deputy Director of the Knight Cancer Institute at Oregon Health and Science University.
The study enrolled 1,717 men with mCRP who had not received treatment for metastatic disease. The two primary endpoints were overall survival and radiographic progression-free survival (assessed by bone and CT scans).
Enzalutamide was associated with a 29% reduction in the risk of death (P<0.0001), and an 81% reduction in the risk of radiographic progression (P<0.0001). Treatment with enzalutamide was also associated with significantly greater responses in soft tissue disease that was measurable on imaging, 59% vs 5% for placebo.
Enzalutamide also prolonged the time before patients needed chemotherapy, which Dr. Beer called a “pragmatic measure of a real-world treatment effect.” Median time to chemotherapy was 28 months with enzalutamide, vs 10.8 months with placebo, a 65% reduction in risk and an absolute benefit of 17 months (P<0.0001).
Grade 3 and 4 adverse events occurred in 43% of the enzalutamide arm and 37% of the placebo arm. The most common adverse events with enzalutamide were back pain, fatigue, constipation and arthralgias, mostly grades 1 and 2. Only 6% of each arm discontinued due to toxicity.
“Because of these positive findings, my view is that enzalutamide provides meaningful clinical benefit” in this setting,” he said in the briefing. “If approved for this indication, it will become an important standard option for use before chemotherapy in patients with asymptomatic or minimally symptomatic advanced prostate cancer,” he went on to say.
Radiotherapy Plus Anti-Androgen Treatment Improves Long-Term Survival
In an updated analysis of the Scandinavian Prostate Cancer Group’s Study VII, the addition of radiotherapy to oral anti-androgen treatment more than halved the 10-year and 15-year prostate cancer-specific mortality rates for men with locally advanced prostate cancer, compared with anti-androgens alone.
Compared with radiotherapy alone, the combination treatment “more than doubles the 10-year survival rate and confirms that this approach should be a standard option for men with this type of prostate cancer who are expected to live at least another 10 years,” said Sophie Dorothea Fosså, Professor of Oncology at Oslo University Hospital in Norway.
The study included 875 patients with locally advanced prostate cancer who received 3 months of total androgen blockade (medical castration); half then received continuous anti-androgen therapy while the other half received continuous anti-androgens plus radiotherapy (70-74 Gy). They were followed for a median of 10.7 years.
Fosså noted that the radiation dose is higher than is typically used in the United States, which may help explain the benefit observed in this study.
The cumulative prostate cancer-specific mortality rate at 10 years was 8% with the combination vs 19% with hormonal therapy alone, a 65% reduction, and at 15 years was 12% and 31%, respectively.
The overall mortality rate was 26% vs 35%, respectively, at 10 years, and 43% and 57%, respectively, at 15 years, she reported. She noted that the 10-year prostate cancer-specific mortality rate of 8% is comparable to results after prostatectomy in comparable patients.
“In these patients, the combination of radiotherapy and hormones may be considered a standard curative treatment option,” she suggested.
Anti-Hypertensive Agent Improves Survival in RCC
A retrospective analysis of patients with metastatic renal cell carcinoma (RCC) found that patients who received an angiotensin system inhibitor (ASI) had improved survival, compared with patients not treated with these agents. When patients also received an agent targeting the vascular endothelial growth factor (VEGF) pathway, survival was further improved, according to Rana McKay, MD, an oncology fellow at Dana Farber Cancer Institute, Boston.
Dr. McKay said the results support the use of ASIs for metastatic RCC patients who are hypertensive and lack contraindications for their use.
The findings came from an analysis of 4,736 patients treated in phase II and III clinical trials. Median overall survival for patients receiving ASIs (n=1,487) was 26.7 months, compared with 17.05 months for those not using ASIs (n=3,249) (HR 1.213; P=0.0009).
Further analysis showed that overall survival was improved in ASI users vs non-users, but was only statistically significant in patients also receiving a VEGF-targeted agent. For this group, median overall survival was 31.12 months versus 21.94 months for non-users (HR 1.380; P=0.0003).
Differences were not significant for users of mTOR-targeted agents or interferon-alpha.
One in Five Cancer Clinical Trials Never Completed
An analysis of cancer clinical trials registered on the web site Clinicaltrials.gov showed that about 20% of trials fail to complete, for reasons unrelated to a drug’s efficacy or toxicity.
Matthew Galsky, MD, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York, reported the findings from an analysis of trials registered on the web site between 2005 and 2011.
He noted, “Trials that are initiated, but fail to complete—ie, close without enrolling the intended number of subjects—represent an extreme example of inefficiency.”
Dr. Galsky and colleagues found that of 7,776 phase II or III interventional trials in adult cancer patients, approximately 20% failed to complete for reasons unrelated to efficacy or toxicity. The main reason was failure to accrue.
Other reasons included inadequate funding, cancellation by the sponsor, and departure of the principal investigator. Fewer than 20% closed because of lack of efficacy or excessive toxicity, and these were excluded from the analysis.
“These failures represent important barriers to progress in cancer care,” he said.
Dr. Galsky commented that this research is “not an indictment of any particular stakeholder,” instead, “we want to hold up a mirror” for the entire clinical trials system. “Clearly, there’s work to do,” he said.
by Caroline Helwick
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