New Findings in Prostate and Kidney Cancers Clarify the Roles of Abiraterone, Finasteride, Bevacizumab, and Surveillance 


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Attendees at the 2013 Genitourinary Cancers Symposium in Orlando, Florida, were brought up to date with the latest news on cancers of the prostate, testes, bladder, and kidney. Below are selected highlights from the meeting describing findings of noteworthy abstracts to extend our regular news coverage.

Benefit of Prechemotherapy Abiraterone in Metastatic Prostate Cancer

Updated results of the randomized COU-AA-302 trial showed that first-line therapy with the CYP17 inhibitor abiraterone (Zytiga) improved survival and slowed disease progression in men with metastatic castration-resistant prostate cancer.1 These updated results support the expanded FDA indication announced in December 2012 for abiraterone plus prednisone as first-line therapy in this setting. In 2011, abiraterone was approved by the FDA for treatment of metastatic castration-resistant prostate cancer following progression on docetaxel chemotherapy.

Time to radiographic progression was twice as long in men who received abiraterone plus prednisone vs prednisone alone (median of 16.5 vs 8.3 months, respectively). More than twice as many men in the abiraterone group achieved at least a 50% decline in prostate-specific antigen levels vs prednisone (69% in the abiraterone group vs 29% of controls). Results favoring abiraterone were consistent across all subgroups.

“Treatment with abiraterone plus prednisone delayed the time to opiate use and chemotherapy use, improves quality of life measures, and remains safe and well tolerated with longer exposures,” stated presenting author Dana E. Rathkopf, MD, medical oncologist at Memorial Sloan-Kettering Cancer Center in New York.

Formal discussant of this trial, William K. Oh, MD, Chief of the Division of Hematology and Medical Oncology, Professor of Medicine and Urology, and the Ezra M. Greenspan, MD, Professor in Clinical Cancer Therapeutics at Icahn School of Medicine at Mount Sinai, New York, said that optimal timing of abiraterone initiation is an important issue. In his view, the overall survival benefit is about 5 months when abiraterone is given either after docetaxel or before, while the radiographic progression-free survival is about 8 months longer with abiraterone as first-line therapy. “It is likely that the maximal benefit of abiraterone is seen when used prior to chemotherapy,” Dr. Oh stated.

Finasteride Reduces Prostate Cancer Risk but Not Mortality

Long-term follow-up of the Prostate Cancer Prevention Trial (PCPT) showed that 7 years of finasteride therapy reduces the risk of a prostate cancer diagnosis but does not affect mortality.2

In the PCPT, finasteride reduced the relative risk of developing prostate cancer by 24.8%, but was associated with a relative risk of 26.9% for developing high-grade prostate cancer. Most doctors stopped recommending finasteride for prevention after results of the study regarding high-grade cancer were published.

A 25% reduction in the diagnosis of prostate cancer with finasteride could have an enormous public health impact, so Phyllis Goodman, MS, Lead Statistician, and colleagues at the Southwest Oncology Group (SWOG) Statistical Center, Seattle, conducted a survival analysis of the randomized trial in the two study arms to determine if finasteride increased risk of death. They hypothesized that an increased risk of death with finasteride would be a potential indicator of a “true” increased risk of high-grade prostate cancer with lethal potential.

At 18 years of follow-up, 5,128 deaths have been reported: 2,584 in the finasteride arm and 2,544 in the placebo arm. In both arms, 78% of men were alive at 15 years. No significant difference was observed in overall survival between the two arms. Ten-year survival from diagnosis for men with prostate cancer was slightly higher in the finasteride arm: 83% vs 81% for placebo. No evidence was found for poorer survival among men with high-grade prostate cancer who were randomly assigned to finasteride.

mTOR Inhibitors Increase Risk of Fatal Events

Mammalian target of rapamycin (mTOR) inhibitors were associated with more than double the number of fatal events in patients with cancer, according to a review of eight clinical trials.3 Three of the trials included patients with renal cell carcinoma, and the other five trials, patients with other types of cancer.

Overall, patients randomly assigned to everolimus (Afinitor) or temsirolimus (Torisel) had a 3.4% incidence of treatment-emergent deaths compared with a cumulative fatality rate of 1% in controls. Looking at renal cell cancer vs other cancers, the fatal event rate on mTOR inhibitors was 3.2% and 3.4%, respectively. The cause of death was unspecified in 61% of fatal adverse events. Sepsis/infection was the most commonly reported cause of death (16%).

Presenting author Toni K. Choueiri, MD, Director of the Kidney Cancer Center at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Boston, said that the risk of death on mTOR inhibitors found in this study was “small but significant,” and he emphasized the overall benefit of these drugs when used for renal cell carcinoma and other approved indications.

“The risks associated with these drugs may be greater once they are introduced to the real-world oncology population,” he noted.

A Medline search was conducted for relevant articles on prospective randomized clinical trials published between 1966 and 2012 and ASCO Annual Meeting abstracts from 2000 to 2012. Eight trials met inclusion criteria: five evaluating everolimus and three evaluating temsirolimus compared to a control drug or placebo. The three trials of renal cell carcinoma included a total of 1,213 patients.

Discussant Sandy Srinivas, MD, Associate Professor of Medicine (Oncology) at Stanford University, Stanford, California, cited several limitations of the meta-analysis, including differences among the trials in the definition and reporting of fatal events, the large number of unspecified deaths, and an incomplete understanding of the biologic mechanisms of mTOR inhibitors.

Single Agent Bests Combination Therapy in RCC

Combination therapy for advanced renal cell carcinoma did not significantly improve outcomes compared with bevacizumab (Avastin) alone and had greater toxicity in a phase II randomized trial of 340 patients with advanced/metastatic renal cell carcinoma (90% had clear cell histology).4

Median duration of progression-free survival was 8.7 months with bevacizumab compared with 7.3 months with bevacizumab/temsirolimus, 7.7 months with sorafenib (Nexavar)/temsirolimus, and 11.3 months with bevacizumab/sorafenib. Although bevacizumab/sorafenib produced longer progression-free survival, the difference between that combination and bevacizumab alone was not statistically significant.

Additionally, bevacizumab/sorafenib was not tolerable. Grade 3 to 5 toxicity rates were 70% to 80% in the combination arms vs 39% with bevacizumab alone.

All three combinations achieved higher response rates, but this did not translate to a progression-free survival advantage, said presenting author David F. McDermott, MD, Director, Biologic Therapy Program, Beth Israel Deaconess Medical Center, and Leader of the Kidney Cancer Program at Dana-Farber Cancer Institute, Boston.

Discussant Sandy Srinivas, MD, Associate Professor of Medicine (Oncology) at Stanford University, Stanford, California, said, “We have reached a ceiling with targeted drugs [in renal cell carcinoma]. Combining drugs in the same class or combining different targeted drugs remains a challenge.”

Surveillance Safe for Small Kidney Masses in Elderly

In older patients, surveillance of small kidney masses is associated with similar cancer-related mortality to that seen with surgery, and surveillance has a lower risk of cardiovascular complications and all-cause mortality. A strategy of surveillance in this setting can spare patients from surgery, according to a retrospective analysis of more than 8,300 elderly patients with small kidney masses.5

These findings are especially important for older sicker patients who may not be able to tolerate surgery, explained presenting author William C. Huang, MD, Assistant Professor of Urologic Oncology at New York University Langone Medical Center, New York.

“Physicians can comfortably tell an elderly patient, especially a patient who is not healthy enough to tolerate anesthesia and surgery, that the likelihood of dying of kidney cancer is low and that kidney surgery is unlikely to extend their lives,” he stated. However, surgery remains an option for elderly patients in excellent health with an extended life expectancy, he added.

The investigators used Surveillance, Epidemiology, and End Results (SEER) registry data linked to Medicare claims for patients aged 66 years or older to identify people diagnosed with small renal masses (ie, under 1.5 inches in diameter). Of 8,317 patients, 5,706 (70%) underwent surgery and 2,611 (31%) underwent surveillance.

At a median follow-up of 4.8 years, 2,078 deaths were reported (25% of the population); 277 deaths (3%) were due to kidney cancer. The rate of kidney cancer–specific death was similar between the surveillance and surgery groups.

In an analysis that controlled for patient and disease characteristics, over time surveillance was associated with a significantly lower risk of death from any cause as well as a lower risk of cardiovascular events. ■

Disclosure: Drs. Rathkopf and Huang and Ms. Goodman reported no potential conflicts of interest. Dr. Oh is a consultant for Jannsen, Medivation, and Astellas. Dr. Choueiri has served in a consulting or advisory role for AVEO, Genentech, GlaxoSmithKline, Novartis, and Pfizer. Dr. McDermott has served in a consulting or advisory role for Genentech and Pfizer.

References

1. Rathkopf DE, Smith MR, De Bono JS, et al: Updated interim analysis of COU-AA-302, a randomized phase III study of abiraterone acetate in patients with metastatic castration-resistant prostate cancer without prior chemotherapy. 2013 Genitourinary Cancers Symposium. Abstract 5. Presented February 14, 2013.

2. Goodman PJ, Thompson IM, Tangen CM, et al: Long-term survival of subjects in the Prostate Cancer Prevention Trial. 2013 Genitourinary Cancers Symposium. Abstract 10. Presented February 14, 2013. 

3. Choueiri TK, Je Y, Sonpavde G, et al: Incidence and risk of treatment-related mortality in patients with renal cell cancer and non-renal cell cancer treated with mammalian target of rapamycin (mTOR) inhibitors. 2013 Genitourinary Cancers Symposium. Abstract 347. Presented February 16, 2013. 

4. McDermott DF, Manola J, Pins M, et al: The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma. 2013 Genitourinary Cancers Symposium. Abstract 345. Presented February 16, 2013.

5. Huang WC, Pinheiro LC, Russo P, et al: Surveillance for the management of small renal masses: Utilization and outcomes in a population-based cohort. 2013 Genitourinary Cancers Symposium. Abstract 343. Presented February 16, 2013.



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