Over the past year, we have seen significant advances in the treatment of prostate, kidney, and urothelial cancers that will benefit patients now and in the future. We have learned about the final results of important clinical trials across multiple genitourinary cancers disease states leading to the approval of novel indications and new drugs by the U.S. Food and Drug Administration (FDA) and improved survival and quality of life for patients with genitourinary cancers.
Xin Gao, MD
For example, several such clinical trials discussed here are the phase III ARAMIS study in nonmetastatic castration-resistant prostate cancer1; KEYNOTE 426 and JAVELIN Renal 101 in renal cell carcinoma2,3; and the phase III JAVELIN Bladder 100 trial in urothelial carcinoma.4 These pivotal trials and others reported between the latter part of 2019 and July 2020 are discussed in this Genitourinary Cancers Almanac edition of The ASCO Post, along with a selection of clinical news and professional perspectives on how such data are impacting patient care.
New Standards of Care in Prostate Cancer
Several studies presented during the past year at the ASCO20 Virtual Scientific Program, the ASCO Genitourinary Cancers Symposium, and other symposia show the progress researchers are making in the treatment of both castration-sensitive and castration-resistant prostate cancers. For more than 73,000 men diagnosed with prostate cancer, their disease will progress to castration-resistant disease. Further, about 40% of these patients will have nonmetastatic prostate cancer with a rising prostate-specific antigen (PSA) level, despite a castrate testosterone level, which is known as nonmetastatic castration-resistant prostate cancer. Approximately one-third of men with nonmetastatic castration-resistant prostate cancer will develop metastases within 2 years. Monitoring of PSA levels is important to identify patients in whom PSA levels are rising and to help offset undertreatment of these men before the disease metastasizes.
In prostate cancer, we now have proof of an overall survival benefit for darolutamide, enzalutamide, and apalutamide for the treatment of patients with high-risk nonmetastatic castration-resistant prostate cancer. These therapies previously demonstrated metastasis-free survival benefits for these patients, but there was some uncertainty about whether that translated to overall survival benefits. Longer-term follow-up data have now established these therapies to confer overall survival improvements while maintaining similar quality-of-life metrics as compared with placebo. The updated data further cement the benefits of a second-generation antiandrogen therapy in patients with high-risk nonmetastatic castration-resistant prostate cancer.
Karim Fizazi, MD, PhD, Head of the Department of Cancer Medicine at the Institut Gustave Roussy in Villejuif, France, presented final overall survival data from the large phase III ARAMIS clinical trial in men with nonmetastatic, castration-resistant prostate cancer, at the ASCO20 Virtual Scientific Program.1 The study evaluated the androgen receptor darolutamide in men with high-risk, nonmetastatic castration-resistant prostate cancer vs placebo. [At the 2019 ASCO Annual Meeting, Fizazi et al reported significantly improved metastasis-free survival in the group receiving darolutamide vs placebo (40.4 months vs 18 months, respectively). The study was published in The New England Journal of Medicine (June 2019),5 and on July 30, 2019, darolutamide was approved for the treatment of patients with nonmetastatic castration-resistant prostate cancer.]
Following publication of the primary analysis, the study was unblinded, and 170 patients crossed over from placebo to darolutamide. Secondary endpoints, including overall survival, were analyzed following the deaths of 254 patients, of whom 15.5% were in the darolutamide arm vs 19.1% assigned to placebo.
Investigators reported a statistically significant improvement in overall survival in patients receiving darolutamide vs placebo. The benefit corresponded with a 31% reduction in mortality compared with placebo. Other secondary endpoints favored the darolutamide arm including delayed pain progression.
New treatment options also became available for patients with metastatic castration-resistant prostate cancer with tumors harboring deleterious BRCA1/2 mutations or other homologous recombination repair (HRR) gene mutations. The randomized PROfound trial showed efficacy of the PARP inhibitor olaparib in patients with alterations in BRCA1, BRCA2, or ATM as well as in a larger population that included patients with alterations in 12 additional prespecified HRR genes.6
The single-arm TRITON2 study demonstrated the efficacy of the PARP inhibitor rucaparib in patients with metastatic castration-resistant prostate cancer who have BRCA-mutated cancers, with an objective response rate of 44%, and 56% of responding patients have a duration of response exceeding 6 months.7 These data led to the FDA approvals of olaparib and rucaparib in May 2020 and establish molecular testing as a standard-of-care for all patients with metastatic castration-resistant prostate cancer.
Advanced Renal Cell Carcinoma
Two phase III trials have shown the benefits of combination therapy vs sunitinib in the first-line treatment of advanced renal cell carcinoma. As reported in The New England Journal of Medicine by Brian I. Rini, MD, of Cleveland Clinic Taussig Cancer Institute, and colleagues, the first interim analysis of the KEYNOTE-426 trial showed significant benefits in overall and progression-free survival with the combination of pembrolizumab plus axitinib vs sunitinib in the first-line treatment of advanced renal cell carcinoma.2
As also reported in The New England Journal of Medicine by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, the first interim analysis of the JAVELIN Renal 101 trial showed the combination of first-line avelumab plus axitinib significantly prolonged progression-free survival vs sunitinib in advanced renal cell carcinoma both among PD-L1–positive patients and all patients.3
On April 19, 2019, pembrolizumab was approved for use in combination with the small-molecule, tyrosine kinase inhibitor axitinib, for the first-line treatment of patients with advanced renal cell carcinoma.
Elizabeth R. Plimack, MD, Chief of the Division of Genitourinary Medical Oncology and Director of Genitourinary Clinical Research at Fox Chase Cancer Center, Philadelphia, presented an extended analysis of the phase III KEYNOTE-426 study at the ASCO20 Virtual Scientific Program.8 Dr. Plimack reported data from the extended analysis that upholds pembrolizumab plus axitinib as a preferred front-line regimen over sunitinib in patients with advanced renal cell carcinoma.
In the extended follow-up of the KEYNOTE-426 study, overall survival in the intention-to-treat population remained significantly improved as compared with sunitinib (hazard ratio = 0.68, P < .001) and was driven by efficacy in the International Metastatic Renal Cell Carcinoma Database Consortium intermediate- or poor-risk patients. Furthermore, the rates of complete response, which were shown to correlate with overall survival, increased to 9% with the longer-term follow-up, including 11% in favorable-risk patients and 8% in the intermediate/poor-risk patients. The extended follow-up data from KEYNOTE-426 further entrench the combination of pembrolizumab plus axitinib as a first-line therapy for patients with advanced clear cell renal cell carcinoma along with the combination of nivolumab plus ipilimumab for patients with intermediate/poor-risk disease.
Ongoing clinical trials are evaluating additional combinations that may further improve outcomes for patients with advanced renal cell carcinoma and are expected to report data in the next 12 to 18 months. These regimens include pembrolizumab plus lenvatinib (CLEAR study); nivolumab plus cabozantinib (CheckMate-9ER study); and nivolumab, ipilimumab, plus cabozantinib (COSMIC-313).9-11
Multiple Breakthroughs in Urothelial Cancer
In urothelial cancer, the treatment landscape changed dramatically over the past year, with three new FDA approvals: pembrolizumab for BCG-unresponsive, high-risk non–muscle-invasive bladder cancer; front-line maintenance avelumab for metastatic urothelial cancer; and enfortumab vedotin for metastatic urothelial cancer previously treated with an anti–PD-1/L1 inhibitor and platinum-containing chemotherapy.
Systemic immunotherapy with pembrolizumab demonstrated a 41% complete response rate in patients with BCG-unresponsive, high-risk non–muscle-invasive bladder cancer with carcinoma in situ in the single-arm KEYNOTE-057 trial.12 Pembrolizumab was granted FDA approval in January 2020 for such patients who are ineligible or who elected not to undergo cystectomy.
Front-line maintenance anti–PD-L1 therapy with avelumab immediately following completion of platinum-based chemotherapy also showed efficacy as compared with best supportive care in the randomized phase III JAVELIN Bladder 100 study, conferring a median overall survival benefit of 21.4 vs 14.3 months (hazard ratio = 0.69, P < .001) in patients with metastatic urothelial cancer.
During the ASCO20 Virtual Scientific Plenary Program, Thomas Powles, MD, PhD, Professor of Genitourinary Oncology and Director of Barts Cancer Centre in London, presented results from the phase III JAVELIN Bladder 100 trial.4 The investigators showed maintenance therapy with the checkpoint inhibitor immunotherapy avelumab significantly extended overall survival in patients with advanced urothelial cancer after first-line chemotherapy. Although avelumab has been shown to be effective in second-line metastatic disease, this study reports the first data demonstrating efficacy of front-line maintenance treatment following initial chemotherapy.
In commenting on the study results during his presentation Dr. Powles said: “The maintenance setting is an attractive time for using a checkpoint inhibitor. Patients have gone through chemotherapy, and the disease is under control. But instead of waiting for the disease to progress after chemotherapy, which it will quickly do in patients with advanced urothelial cancer, adding avelumab significantly improves survival.”
Finally, for patients with treatment-refractory metastatic urothelial cancer, the nectin-4–directed antibody-drug conjugate enfortumab vedotin demonstrated efficacy in the single-arm EV-201 trial, showing an objective response rate of 44%, including 12% complete responses. Enfortumab vedotin was granted accelerated approval by the FDA in December 2019.
Dr. Gao is a medical oncologist and clinical investigator at Mass General Cancer Center in Boston. He specializes in providing high-quality care for patients with cancers of the genitourinary system. In addition, Dr. Gao is actively involved in clinical trials evaluating new targeted therapies and immunotherapies for patients with cancers of the kidneys, bladder, and prostate.
DISCLOSURE: Dr. Gao has received advisory board consulting honoraria from Exelixis andDendreon.
1. Fizazi K, et al: Overall survival results of phase III ARAMIS study of darolutamide added to androgen deprivation therapy for nonmetastatic castration-resistant prostate cancer. ASCO20 Virtual Scientific Program. Abstract 5514.
2. Rini BI, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116-1127, 2019.
3. Motzer RJ, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1103-1115, 2019.
4. Powles T, et al: Maintenance avelumab + best supportive care (BSC) vs BSC alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma. ASCO20 Virtual Scientific Program. Abstract LBA1. Presented in premeeting press briefing on May 26, 2020.
5. Fizazi K, et al: Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 380:1235-1246, 2019.
6. de Bono J, et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382:2091-2102, 2020.
7. Abida W, et al: Preliminary results from the TRITON2 study of rucaparib in patients with DNA damage repair-deficient metastatic castration-resistant prostate cancer. Ann Oncol 30:327-328, 2019.
8. Plimack ER, et al: Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma. ASCO20 Virtual Scientific Program. Abstract 5001.
9. Hutson TE, et al: A phase II study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. ASCO20 Virtual Scientific Program. Abstract 685.
10. Bristol Myers Squibb and Exelixis announce positive topline results from pivotal phase III CheckMate-9ER trial evaluating Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) in previously untreated advanced renal cell carcinoma [news release]. April 20, 2020. Available at news.bms.com. Accessed April 20, 2020.
11. Choueiri TK, et al: A phase III study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor-risk. ASCO20 Virtual Scientific Program. Abstract TPS5102.
12. Balar AV, et al: KEYNOTE-057. 2019 Genitourinary Cancers Symposium. Abstract 350. Presented February 15, 2019.