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Genitourinary Cancers Symposium 2018
This year’s Genitourinary Cancers Symposium, co-sponsored by the American Society of Clinical Oncology (ASCO), American Society for Radiation Oncology, and Society of Urologic Oncology, took place in San Francisco from February 8 to 10. We review sessions on advances in renal cell carcinoma and prostate cancer.
IMmotion151: A Randomized Phase 3 Study of Atezolizumab Plus Bevacizumab Versus Sunitinib In Untreated Metastatic Renal Cell Carcinoma
- Robert Motzer, MD, Memorial Sloan Kettering Cancer Center, New York, New York
In patients with untreated programmed death ligand-1–positive (PD-L1+) advanced renal cell carcinoma (RCC), progression-free survival (PFS) was improved with the combination of atezolizumab (Tecentriq, Genentech) and bevacizumab (Avastin, Genentech) compared with sunitinib (Sutent, Pfizer) in the IMmotion151 trial. Atezolizumab is a fully humanized monoclonal antibody of the immunoglobulin G1 isotype against PD-L1, Dr. Motzer said in a symposium press-cast.
The vascular endothelial growth factor (VEGF) inhibitor bevacizumab, which has some single-agent activity, is approved for first-line use in metastatic RCC (mRCC) in combination with interferon-alpha-2a. Atezolizumab has demonstrated antitumor activity and a tolerable safety profile in mRCC. A randomized phase 2 study indicated synergy and encouraging efficacy for the atezolizumab/bevacizumab combination versus sunitinib in PD-L1+ patients. Dr. Motzer speculated that atezolizumab’s T-cell–mediated cancer cell killing may be enhanced through bevacizumab’s reversal of VEGF-mediated immunosuppression.
IMmotion151 investigators randomized 915 patients in the phase 3 trial to either atezolizumab (1,200 mg intravenously [IV] once every three weeks) and bevacizumab (15 mg/kg IV once every three weeks) or sunitinib (50 mg orally once daily for four weeks on and then two weeks off). Patients were stratified by PD-L1 status: less than 1% or 1% or greater PD-L1 expression on tumor-infiltrating immune cells (IC).
The coprimary endpoints were PFS (based on RECIST v1.1 criteria) in PD-L1+ patients with 1% or greater IC and overall survival (OS) in intent-to-treat (ITT) patients. In the ITT population, 362 were PD-L1+. Median age was 62 years in the combination therapy group and 59 years in the sunitinib group. Sixty-seven percent were men. Nearly three-quarters of the patients were in the intermediate-risk category based on Memorial Sloan Kettering Cancer Center risk criteria.
PFS in the PD-L1+ group was a median of 11.2 months (95% confidence interval [CI], 8.9–15.0) compared with 7.7 months in the sunitinib group (hazard ratio [HR], 0.74; 95% CI, 6.8–9.7; P = 0.02). The secondary endpoint of PFS in the ITT population was 11.2 months for the atezolizumab/bevacizumab arm and 8.4 months for the sunitinib arm (HR, 0.83; 95% CI, 0.70–0.97). Independent review committee assessment of PFS in the PD-L1+ arm showed a smaller benefit for the combination (8.9 months versus 7.2 months). All assessments were blinded to PD-L1 status.
Confirmed objective response rates were 43% and 35% in the combination and sunitinib arms, respectively, for PD-L1+ patients. In addition, median duration of response has not been reached in the atezolizumab/bevacizumab arm and was 12.9 months in the sunitinib arm. Sixty-five percent of combination arm patients have an ongoing response versus 53% in the sunitinib arm.
OS data, while immature, revealed a trend favoring the atezolizumab/bevacizumab combination in the ITT population (HR, 0.8; P = 0.09) and in the PD-L1+ population (not reached versus 23.3 months; HR, 0.68).
Safety results were similar in all treated patients and in those with PD-L1+ disease. Grade 3–4 adverse event rates were 40% and 54% in the combination and sunitinib populations, respectively. Sixteen percent of patients treated with atezolizumab/bevacizumab required systemic corticosteroid use within 30 days of an adverse event of special interest (rash, abnormal thyroid, adrenal insufficiency, liver function test abnormalities, colitis, pneumonitis). Time to symptom interference with activities of daily living in the ITT population was 11.3 months and 4.3 months for the combination and sunitinib groups, respectively.
“These study results support atezolizumab plus bevacizumab as a first-line treatment option for patients with PD-L1 advanced RCC,” Dr. Motzer concluded.
ASCO moderator Sumanta K. Pal, MD, of City of Hope in Duarte, California, commented that the results compared favorably with those for the nivolumab/ipilimumab (Opdivo/Yervoy, both Bristol-Myers Squibb) combination, but that with the latter combination, 60% of patients needed steroids.
Apalutamide Treatment and Metastasis-Free Survival in Prostate Cancer
- Eric J. Small, MD, Helen Diller Family Comprehensive Center, University of California, San Francisco, California
In the phase 3 SPARTAN trial among men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC), apalutamide (Erleada, Janssen) decreased the risk of death and prolonged metastasis-free survival (MFS) compared with placebo, Dr. Small said in a press briefing.
He noted that metastatic CRPC is a uniformly fatal disease, with a median survival of approximately 2.5 years. It can develop from metastatic hormone-sensitive prostate cancer or from nonmetastatic prostate cancer that has developed resistance to androgen deprivation therapy.
Apalutamide is a next-generation oral competitive inhibitor of the androgen receptor developed for the treatment of patients with prostate cancer. It prevents binding of androgens to the androgen receptor and translocation of the androgen receptor to the nucleus, while impeding androgen receptor-mediated DNA transcription. The aim of the SPARTAN study was to see if the development of metastases and the transition from nonmetastatic to metastatic CRPC could be slowed with apalutamide.
SPARTAN investigators enrolled 1,207 men with nonmetastatic CRPC and prostate-specific antigen doubling time (PSADT) of 10 months or less, an indicator of high risk for metastatic disease and prostate cancer-specific death. Median age was 74 years, and PSADT was six months or less in 71% of patients. They were randomized double-blind 2:1 to apalutamide (240 mg once daily) or placebo. The primary endpoint was MFS, defined as the time from randomization to first radiographic distant metastasis (per blinded central review) or death. Secondary endpoints included time to metastasis, progression-free survival, time to symptomatic progression, and overall survival. Patients were eligible to receive study-provided open-label abiraterone acetate (Zytiga, Janssen) plus prednisone after developing distant metastases.
Median MFS, the primary endpoint, was 40.5 months in the apalutamide group and 16.2 months in the placebo group, a 72% risk reduction (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.23–0.35; P < 0.0001). The benefit was observed across all subgroups. The secondary endpoint of median time to metastasis was reduced by 73% in the apalutamide group (40.5 months versus 16.6 months; HR, 0.27; 95% CI, 0.22–0.34; P < 0.0001). Risk of local progression, distant progression, or death was reduced by 71% in the apalutamide group, and time to symptomatic progression was also reduced significantly (55%; P < 0.0001) in the apalutamide-treated patients. An immature overall survival analysis showed a 30% risk reduction for death (P = 0.07).
Dr. Small also noted a 94% risk reduction in time to PSA progression among patients receiving apalutamide (apalutamide not yet reached versus placebo 3.7 months; P < 0.0001).
Grade 3–4 adverse events were reported in 45% of patients receiving apalutamide and in 34% of those receiving placebo. Discontinuation rates for adverse events were 11% and 7% for apalutamide and placebo, respectively. Fatigue (30.4%) and rash (23.8%) were the most common adverse events in the apalutamide group. “The addition of apalutamide to androgen deprivation therapy was well tolerated, with maintained health-related quality of life,” Dr. Small said.
He concluded, “Overall, these data suggest that apalutamide should be considered as a new standard of care for men with high-risk nonmetastatic CRPC.”
Moderator Sumanta K. Pal, MD, of City of Hope in Duarte, California, commented, “Dr. Small’s dataset shows that apalutamide, a very potent hormonal therapy, delays the risk of metastasis or death by 72%—a very clinically meaningful finding. Moreover, the drug appeared to be very well tolerated.”
Editor’s note: Based upon the SPARTAN trial, the Food and Drug Administration approved apalutamide on February 14, 2018.
PROSPER: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide in Men With Nonmetastatic Castration-Resistant Prostate Cancer
- Maha Hussain, MD, Northwestern University, Chicago, Illinois
Among men with nonmetastatic castration-resistant prostate cancer (M0 CRPC) and rapidly rising prostate-specific antigen (PSA), treatment with enzalutamide (Xtandi, Astellas) led to clinically meaningful and statistically significant reductions in risk for developing prostate cancer metastases in the global, multicenter, phase 3 PROSPER trial.
Dr. Hussain said increasing baseline PSA and a PSA doubling time of less than 10 months predict development of metastases. Median bone metastasis-free survival (MFS) is 25–30 months. “Delaying time to all metastases is clinically relevant, with potential to delay cancer-related morbidity and prolong overall survival (OS),” she said.
In the prior PREVAIL trial in men with chemotherapy-naïve metastatic CRPC, enzalutamide significantly improved OS and radiographic progression-free survival (rPFS). In the STRIVE trial, enzalutamide was superior to bicalutamide in improving rPFS in patients with chemotherapy-naïve M0 CRPC.
The PROSPER trial hypothesis, Dr. Hussain said, was that enzalutamide would delay metastasis development in men with M0 CRPC and rapidly rising PSA (doubling time of 10 months or less). Investigators randomized 1,401 men (mean age, approximately 74 years) with M0 CRPC, baseline PSA of 2 ng/mL or greater, and PSA doubling times of 10 months or less 2:1 to enzalutamide 160 mg per day or placebo. All patients received androgen deprivation therapy (ADT). The primary endpoint was MFS (defined as time from randomization to radiographic progression or death within 112 days of treatment discontinuation).
The median duration of therapy was 18.4 months in the enzalutamide arm and 11.1 months in the placebo arm. PSA doubling was less than six months in 77% of patients. Treatment discontinuation rates for adverse events were low (enzalutamide 9% versus placebo 6%). Grade 3 or higher adverse event rates were 31% in the enzalutamide group and 23% in the placebo group. The most frequently reported events were hypertension (5% enzalutamide versus 2% placebo) and fatigue (3% enzalutamide versus 1% placebo). Three percent of deaths in the enzalutamide arm were attributed to drug therapy compared with 1% in the placebo arm.
The primary endpoint of median MFS was 36.6 months in the enzalutamide plus ADT arm and 14.7 months in the placebo plus ADT arm (hazard ratio [HR], 0.29; 95% confidence interval, 0.24–0.35; P < 0.0001). “This was a 71% reduction in relative risk of radiographic progression or death,” Dr. Hussain said. The enzalutamide plus ADT benefit was consistent across all subgroups. Time to PSA progression also favored enzalutamide at 37.2 months versus 3.9 months for placebo (HR, 0.07; P < 0.0001).
The first interim analysis of OS revealed a nonsignificant 20% reduction in the relative risk of death with enzalutamide versus placebo. Median OS was not yet reached in either group.
Progression events (new bone metastases, new soft-tissue metastases, both, or death without documented radiographic progression) were reported in 23% and 49% of patients in the enzalutamide and placebo groups, respectively.
“The proportion of progression events in the enzalutamide arm was 50% less than that of the placebo arm,” Dr. Hussain observed.
She concluded, “In men with M0 CRPC and rapid PSA doubling time (median, 37 months), enzalutamide resulted in a clinically meaningful and statistically significant 71% reduction in the relative risk of developing M1 CRPC.”