Final survival results from three randomized, placebo-controlled trials, along with a safety analysis across all three, are helping to clarify the treatment landscape for nonmetastatic castration-resistant prostate cancer (nmCRPC). The results will be presented during the ASCO20 Virtual Scientific Program.
SPARTAN
In the first trial, apalutamide was found to offer a significant survival benefit over placebo even after crossover to the active agent was allowed (Abstract 5516).
The SPARTAN trial evaluated apalutamide versus placebo in patients with nmCRPC and a prostate-specific antigen doubling time of 10 months or fewer who were also receiving androgen deprivation therapy. The primary endpoint of metastasis-free survival was previously reported and showed significant benefit with apalutamide. Eric J. Small, MD, of the Hellen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, will present the new final survival results, including patients who crossed over to apalutamide upon the study’s unblinding.
The study included 1,207 patients, randomly assigned to receive either apalutamide (240 mg once per day; 806 patients) or placebo (401 patients). A total of 76 patients receiving placebo crossed over to receive apalutamide, and the study had a median follow-up period of 52 months.
The median overall survival (OS) with apalutamide was 73.9 months, compared with 59.9 months with placebo (HR 0.784; p = 0.0161). In an OS analysis censoring patients who crossed over, the placebo group had a median OS of 52.8 months (HR 0.685; p = 0.0002). The time to cytotoxic chemotherapy was also improved with apalutamide; although the median was not reached in either group, the HR favoring apalutamide was 0.629 (p = 0.0002).
“These are very important results for two reasons,” Dr. Small told ASCO Daily News. First of all, there had been concern that delaying metastasis might not be clinically significant. “We knew that delaying metastases was not the only story, since we had previously shown a significant improvement in delay of symptoms, which is very important to our patients, but nevertheless the question of a clinically relevant result persisted,” Dr. Small said. “These data lay that issue to rest, as there is an unambiguous survival advantage.”
Second, Dr. Small said that the survival advantage persisted even though at least 80% of the patients in the placebo group went on to receive life-prolonging therapy either at progression or with crossover to apalutamide when the study was unblinded. He added that this means the results cannot be attributed to one group receiving an active agent and the placebo group never receiving one.
“In other words, this was very much a study of an active agent (apalutamide) early versus an active agent later, and earlier leads to improved survival,” Dr. Small said.
Dr. Small added that there were no new safety signals in this latest analysis of the SPARTAN trial. A total of 15.2% of patients receiving apalutamide discontinued therapy because of adverse events, compared with 8.4% in the placebo group. Grade 3/4 treatment-emergent adverse events of special interest were rash (5.2%), fractures (4.9%), falls (2.7%), and ischemic heart disease (2.6%). One treatment-emergent adverse event leading to death, a myocardial infarction, was considered potentially related to apalutamide.
“We have also learned from this study and others like it that men with nonmetastatic prostate cancer are at risk for osteoporotic events, such as fracture, and need antiresorptive therapy as a standard of care,” Dr. Small said.
ARAMIS
In another trial’s (ARAMIS) final survival analysis, results showed that the androgen receptor inhibitor darolutamide also offered significant OS improvement over placebo, as well as delayed onset of cancer-related symptoms and subsequent chemotherapy (Abstract 5514). The results will be presented by Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, in Villejuif, France.
The trial included 1,509 patients with nmCRPC randomly assigned to receive either darolutamide (600 mg twice daily; 955 patients) or placebo (554 patients) while continuing androgen deprivation therapy. A previous report found significantly prolonged metastasis-free survival with darolutamide versus placebo (median 40.4 months compared with 18.4 months, respectively). As with the SPARTAN trial, crossover was allowed when the study was unblinded after the primary analysis; a total of 170 patients crossed over from placebo to darolutamide.
At the final analysis, the median OS was not reached in either study arm; however, darolutamide significantly reduced the risk of death by 31% (HR 0.69, 95% CI [0.53, 0.88]; p = 0.003). The median time to first cytotoxic chemotherapy was also not reached in either arm (HR favoring darolutamide 0.58, 95% CI [0.44, 0.76]; p < 0.001). In addition, the median time to first symptomatic skeletal event was not reached (HR 0.48, 95% CI [0.29, 0.82]; p = 0.005).
The safety profile was similar to previous reports, and the incidences of adverse events of interest, including falls, central nervous system effects, and hypertension, were no different than placebo after adjustment for treatment exposure.
“For the first time in men with nonmetastatic disease, a systemic treatment besides androgen deprivation therapy, darolutamide, improves OS,” Dr. Fizazi said.
“For the first time in men with nonmetastatic disease, a systemic treatment besides androgen deprivation therapy, darolutamide, improves OS,” Dr. Fizazi said.
He highlighted that darolutamide provides other clinical benefits in addition to prolonging survival for men with M0 CRPC, for whom the development of metastases can cause cancer-related symptoms that affect their daily lives or impose the burden of additional treatments.
“In ARAMIS, incidences of key adverse events known to be associated with androgen receptor inhibitors showed small or no differences between the darolutamide and placebo groups,” Dr. Fizazi said. “This is obviously a major advantage with darolutamide in this population of men, together with its efficacy in both metastasis-free survival, the primary endpoint, and OS, the most important endpoint in oncology.”
PROSPER
Similar to SPARTAN and ARAMIS, a previous report from the PROSPER trial found improved metastasis-free survival with enzalutamide compared with placebo. The new final survival analysis again showed that the metastasis-free survival benefit did translate into an OS benefit of almost 1 year in patients with nmCRPC who received enzalutamide (Abstract 5515). The results will be presented by Cora N. Sternberg, MD, of Weill Cornell Medicine and NewYork-Presbyterian Hospital.
PROSPER included men with nmCRPC, a PSA doubling time of 10 months or less, and PSA of at least 2 ng/mL at screening; they were randomly assigned 2:1 to receive enzalutamide or placebo, and all men continued receiving ADT.
The HR for OS favoring enzalutamide was 0.73 (95% CI [0.61, 0.89]; p = 0.0011). The median OS was 67.0 months with enzalutamide and 56.3 months with placebo, despite the fact that patients received subsequent life-prolonging therapy in both arms.
The median duration of study treatment was 33.9 months with enzalutamide and 14.2 months with placebo. A total of 303 patients in the placebo group (65%) received subsequent neoplastic therapy. Eight-four percent of patients in the placebo group received at least one treatment after study-assigned therapy; 33% of those in the enzalutamide group received at least one subsequent anti-neoplastic therapy.
“The safety profile was consistent with the established safety profile of enzalutamide,” Dr. Sternberg said. Grade 3 or higher adverse events occurred in 48% of men in the enzalutamide group and in 27% of those in the placebo group; 16% and 6%, respectively, were drug-related adverse events. Adverse events that had an event rate per 100 patient-years that were at least two points higher with enzalutamide included falls (9 per 100 patient-years vs. 4), fatigue (14 vs. 12), and hypertension (7 vs. 5).
“These data are reassuring because OS was improved with enzalutamide in patients with nmCRPC,” Dr. Sternberg said.
Safety Comparison Across Trials
Finally, an analysis of all three trials confirmed Dr. Fizazi’s point regarding safety, finding that darolutamide has a favorable safety profile compared with the other two agents (Abstract 5561).
The analysis, which will be presented by Neal D. Shore, MD, FACS, director of the Carolina Urologic Research Center, used a matching-adjusted indirect comparison that adjusts for cross-trial heterogeneity.
Coauthor Susan Halabi, PhD, of Duke University and the Duke Cancer, told ASCO Daily News that although this approach does adjust for observed variables, it cannot adjust for unobserved variables across trials or variables reported in only one trial.
“Another limitation is that one cannot match for differences in study design [and] administration of drug, and this may lead to differences in results,” Dr. Halabi said. “Our goal is to minimize bias and conduct sensitivity analyses to enhance the robustness of the results.”
In this new analysis, darolutamide had a significantly lower risk for fall, rash, and fracture compared with apalutamide. The risk difference [RD] for fall was -6.3%, for rash -16.0%, and for fracture -6.2% (p < 0.05 for all).
When compared with enzalutamide, darolutamide showed significantly lower risk with regard to fall (RD -6.3%), dizziness (RD -4.9%), mental impairment (RD -3.5%), hypertension (RD -3.9%), fatigue (RD -12.8%), and severe fatigue (RD -2.2%; p < 0.05 for all).
“Given the preclinical evidence, that darolutamide has markedly lower blood–brain barrier penetration, the decrease in the spectrum of neurocognitive side effects was not surprising, and was consistent with our hypotheses,” Dr. Shore said.
Dr. Halabi added that although indirect comparisons can be useful, head-to-head trials are still needed.
“Phase III clinical trials are the gold standard design and provide the strongest evidence for comparing the efficacy and safety across treatment arms,” she said.
— Dave Levitan
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