Tomasz M. Beer, MD, discusses Abstract LBA1 “Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study."

The 2014 Genitourinary Cancers Symposium was held January 30-February 1, in San Francisco, California. The following highlights are courtesy of the Genitourinary Cancers Symposium Daily News team (gucasym.asco.org/dn).

This year marked the 10th anniversary of the Genitourinary (GU) Cancers Symposium, which brings together thousands of attendees from around the globe to exchange ideas, best practices, and research that will lead to future progress in GU cancers. The 2014 Symposium, which focused on "Integrating Biology Into Patient-Centered Care," saw a record attendance of more than 3,100 surgical, medical, and radiation specialists, 53% of whom travelled from outside the United States.

The Symposium also featured six "Decades in Review" lectures which addressed the great progress made in GU cancer research over the past 10 years. The lectures focused on advances and challenges within each subspecialty: prostate cancer, urothelial carcinoma, and renal cancer, as well as penile, urethral, and testicular cancers.

The scientific and educational presentations featured at the Symposium likewise highlighted the challenges and triumphs of the past decade, as well as showcased the latest science, indicating future directions of the field.

Prostate cancer

One of the most exciting studies to be presented at the Symposium, the phase III PREVAIL trial looked at the effects of 160 mg/day of enzalutamide on patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) that progressed on androgen deprivation therapy (ADT). A total of 1,717 chemotherapy-naïve patients were randomly assigned to receive 160 mg/day of enzalutamide or placebo in a double-blind fashion (Abstract LBA1). An interim analysis uncovered such dramatic improvements with enzalutamide in overall survival (OS) and radiographic progression-free survival (PFS)—the co-primary endpoints of the study—that the investigators stopped the trial early in October 2013 and offered enzalutamide to the patients in the placebo arm at the behest of the Independent Data Monitoring Committee. After a median follow-up of 20 months, enzalutamide significantly reduced the risk of death by 29% (HR: 0.706; 95% CI [0.60-0.84]; p < 0.0001) and slashed the risk of radiographic progression by 81% (HR: 0.186; 95% CI [0.15-0.23]; p < 0.0001). In addition, enzalutamide succeeded in completely or partially reducing soft tissue disease on imaging in 59% of patients, as compared with 5% in patients assigned to placebo (p < 0.0001). Perhaps the crowning achievement of the trial was that, compared to the placebo, enzalutamide delayed the median time to chemotherapy initiation from 10.8 months to 28.0 months (HR: 0.35; 95% CI [0.30-0.40]; p < 0.0001).

A retrospective analysis of the CA184-043 study suggests that ipilimumab may work best in patients with mCRPC who have a favorable prognostic profile. For these patients, ipilimumab provides durable disease control that improves OS on the order of four to seven months (Abstract 2). In a posthoc analysis conducted among patients with an alkaline phosphatase level less than 1.5 times the upper limit of normal, a hemoglobin level of at least 11 mg/dL, and no visceral metastases, median OS reached 22.7 months with ipilimumab as compared with 15.8 months with placebo (HR: 0.62; 95% CI [0.45-0.86]). Updated results from the randomized phase III Prostate Cancer Study IV trial show that for men with high-risk prostate cancer, reducing the period of androgen deprivation therapy (ADT) from 36 months to 18 months improves select quality-of-life outcomes without compromising survival (Abstract 5).

Urothelial carcinoma and urethral, penile, and testicular cancers

Researchers within The Cancer Genome Atlas Bladder Cancer Working Group have successfully analyzed 131 high-grade muscle-invasive urothelial carcinomas not previously exposed to cytotoxic chemotherapy (Abstract 285). Their results paint an intricate picture of the multiple molecular players altered in this potentially lethal version of the disease. The study also brings to light promising actionable targets, such as HER2, that may open the door to other more-personalized therapeutic options beyond cisplatinbased chemotherapy.

Renal cell cancer

According to a retrospective study, angiotensin system inhibitors (ASIs) yield more than a nine-month improvement in survival when used by patients with metastatic renal cell carcinoma (mRCC) receiving a VEGF inhibitor to treat their disease (Abstract 437). Patients on anti-VEGF treatment who did not receive ASI showed a median OS duration of 20.21 months; for those who received ASI, OS duration reached 31.12 months (HR: 1.357; 95% CI [1.179- 1.562]; p < 0.0001). All data was adjusted for the development of VEGF inhibitor– associated hypertension. ASI use in the setting of mRCC treatment with mTOR inhibitors or cytokines did not significantly alter survival outcomes, suggesting synergy between VEGFtargeted therapy and ASIs.

The randomized phase III SWITCH trial showed that patients with mRCC who start on sorafenib and then switch to sunitinib upon progression have the same outcomes as patients who start on sunitinib and switch to sorafenib upon progression (Abstract 393). The median total PFS duration over the two sequential therapies reached 12.5 months in the sorafenib-sunitinib arm and 14.9 months in the sunitinibsorafenib arm (p = 0.54). Median OS likewise showed similar results, reaching 31.5 months in the sorafenibsunitinib arm and 30.2 months in the sunitinib-sorafenib arm (p = 0.49).

Additional research highlights

Another important study presented at the Symposium addressed a problem that affects all cancer types: the high number of trials that fail to reach completion, largely due to poor patient accrual (Abstract 288). The study, which came out of the Icahn School of Medicine at Mount Sinai, determined the scope of the problem among U.S. cancer clinical trials by identifying all phase II or III interventional cancer trials listed in the ClinicalTrials.gov database that started between September 2005 and November 2011. A total of 7,776 studies met the inclusion criteria for analysis, including 740 GU cancer trials. The investigators then focused on those trials that were "terminated" or "withdrawn" and the reasons as to why. Of the 7,776 studies, 935 trials enrolling roughly 48,000 patients failed to reach completion. The most common reason for trials failing to complete was poor patient accrual (39%). However, logistical problems (21%) and unexpected toxicity and efficacy signals (18%) also exerted a strong influence. Using the Kaplan- Meier methodology, the cumulative incidence of premature termination of adult cancer clinical trials reached 20% at seven years (95% CI [18%- 22%]). Notably, trials conducted in GU cancer, including those in bladder cancer, were not more likely to end early compared with other cancer types.

"Based on this analysis and others, it's apparent that we need better collaboration and communication within the system, and we need novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades," said senior investigator Matthew D. Galsky, MD, during a press conference detailing thestudy results.

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