IN TWO SEPARATE TRIALS presented at the 2018 Genitourinary Cancers Symposium, apalutamide and enzalutamide (Xtandi), respectively, reduced the risk of metastasis and prolonged metastasis-free survival in men with high-risk nonmetastatic castrate-resistant prostate cancer. In the SPARTAN trial,1,2 apalutamide reduced the risk of developing metastasis and death by 72% compared with placebo, and in the PROSPER trial,3 enzalutamide reduced the risk of metastasis or death by 71% compared with placebo. In both studies, men were treated with ongoing androgen-deprivation therapy. [Editor’s Note: On February 14, the U.S. Food and Drug Administration (FDA) approved apalutamide (Erleada) for the treatment of patients with nonmetastatic castration-resistant prostate cancer. This is the first FDA-approved treatment for this patient population.]
Some physicians advocate watchful waiting in men with nonmetastatic castrate-resistant prostate cancer, but a rapidly rising prostate-specific antigen (PSA) on androgen-deprivation therapy (doubling time of less than 8–10 months) places men at significantly greater risk of developing metastases and death, and this was the patient population enrolled in both the SPARTAN and PROSPER trials.
SPARTAN Study
Eric J. Small, MD
“THESE DATA demonstrate that the use of apalutamide prior to the development of metastases clearly benefited patients whose prostate cancer no longer responded to conventional hormonal therapy. It is exciting there now exists such a well-tolerated agent for this group of high-risk patients for whom no approved therapies currently exist,” said lead author of the SPARTAN trial, Eric J. Small, MD, of the University of California, San Francisco.
The SPARTAN study enrolled 1,207 men with nonmetastatic castrate-resistant prostate cancer who stopped responding to androgen-deprivation therapy and were at high risk of metastasis, with a PSA doubling time of 10 months or less, and randomized them in a 2:1 ratio to receive oral apalutamide vs placebo added to ongoing androgen-deprivation therapy. When metastases developed, second therapies were added, and patients could opt to receive on-study abiraterone (Zytiga) plus placebo, a standard of care. The study blind was not broken at the time metastasis developed.
“It is exciting there now exists such a well-tolerated agent [apalutamide] for this group of high-risk patients for whom no approved therapies currently exist.”— Eric J. Small, MD
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At study entry, median PSA doubling time was 4.5 months in both arms. Apalutamide reduced the risk of metastasis and death by 72% compared with placebo and significantly prolonged median metastasis-free survival by 2 years (40.5 months in the apalutamide group vs 16.2 months in the placebo group, P < .001). Apalutamide significantly improved the time to metastasis, progression-free survival, and symptom progression compared with placebo. In fact, there was a 55% risk reduction in the time to symptomatic disease progression (P < .001). A consistent benefit of apalutamide was observed in all subgroups.
Although subsequent FDA-approved treatment was administered to 80% of placebo recipients, apalutamide was still associated with improvements in time to symptomatic progression and second progression-free survival. It is too early to establish a survival benefit, but a trend toward improved survival was observed in the apalutamide-treated group. At a median follow-up of 20.3 months, 61% of the apalutamide group and 30% of the placebo group were still on therapy.
Apalutamide was well tolerated, and quality-of-life scores were maintained when the drug was added to androgen-deprivation therapy. The most common adverse events in the apalutamide group were fatigue, hypertension, rash, and diarrhea.
Sumanta Pal, MD
“Until now, the optimal management of patients with prostate cancer and no visible evidence of spread with a rise in blood markers remained an enigma. These finding suggest there may finally be a treatment that holds real promise for extending their health and their lives,” said ASCO expert Sumanta Pal, MD, of City of Hope, at a premeeting press briefing.
PROSPER Trial
THE PROSPER TRIAL enrolled a similar patient population as the SPARTAN trial—1,401 men with nonmetastatic castrate-resistant prostate cancer and a rapidly rising PSA (PSA doubling time of 10 months or less). Men continued on androgen-deprivation therapy and were randomized 2:1 to receive enzalutamide or placebo. The primary endpoint was metastasis-free survival.
Baseline characteristics were well balanced between the two treatment arms. This was an older population, with a median age of about 73 years, and some men were in their 90s. The median PSA doubling time was 3.8 months in the enzalutamide arm and 3.6 months in the placebo arm.
“This was a relatively high-risk population. More than 75% in both arms had PSA doubling times less than 6 months,” said lead author of the PROSPER trial, Maha Hussain, MD, FACP, FASCO, of Northwestern University, Chicago. Dr. Hussain presented data as of June 2017.
Maha Hussain, MD, FACP, FASCO
She noted that in February 2018, 61% of men were still taking enzalutamide and 28% were on placebo. For the primary endpoint, the median metastasis-free survival was 36.6 months for enzalutamide vs 14.7 months for placebo, representing a 71% relative risk reduction (P < .0001).
The median time to use of new antineoplastic therapy was significantly longer with enzalutamide: 39.6 months vs 17.7 months, a 79% relative risk reduction (P < .0001). The time to PSA progression was also significantly longer with enzalutamide: median of 37.2 months vs 3.9 months, respectively (P < .0001). With a short follow-up of 22 months, median overall survival was not yet reached in either arm. However, there was a trend toward improved survival with enzalutamide.
The benefits of enzalutamide were evident across all subgroups. “These findings are clinically meaningful,” she stated.
“The benefits of enzalutamide were evident across all subgroups. These findings are clinically meaningful.”— Maha Hussain, MD, FACP, FASCO
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As expected, adverse events of any grade were higher in the enzalutamide-treated group: 87% vs 77% for placebo. Grade 3 or higher adverse events were reported in 31% vs 23%, respectively. Serious adverse events were reported in 24% vs 18%, respectively. The rate of treatment discontinuation due to adverse events was 10% with enzalutamide vs 8% with placebo. Deaths due to adverse events were reported in 3% and 1%, respectively.
Adverse events of special interest (any grade) that were higher in the enzalutamide group follow: hypertension, 12% vs 5%, respectively; major cardiovascular disease, 5% vs 3%, respectively; mental impairment, 5% vs 2%, respectively. These rates were higher in patients with comorbidities, she said. ■
DISCLOSURE: Dr. Small has stock or other ownership interests in Fortis and Harpoon Therapeutics, has had a consulting or advisory role with Fortis, Gilead Sciences, and Valeant Pharmaceuticals, and has received honoraria from Janssen-Cilag and institutional research funding from Janssen. Drs. Pal and Hussain reported no conflicts of interest.
REFERENCES
1. Small EJ, Saad F, Chowdhury S, et al: SPARTAN, a phase 3 double-blind, randomized study of apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer. 2018 Genitourinary Cancers Symposium. Abstract 161. Presented February 8, 2018.
2. Smith MR, Saad F, Chowdhury S, et al: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. February 8, 2018 (early release online).
3. Hussain M, Fizazi K, Saad F, et al: PROSPER: A phase 3 randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer. 2018 Genitourinary Cancers Symposium. Abstract 3. Presented February 8, 2018.
