Dr. Maha Hussain presents Abstract 3.
Dr. Eric J. Small presents Abstract 161.
Dr. Philip W. Kantoff discusses Abstracts 3 and 161.
“Nonmetastatic (M0) castration-resistant prostate cancer is an area of unmet need with no currently approved therapies,” Maha Hussain, MD, FACP, FASCO, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, said while presenting results of the phase III PROSPER trial on February 8.
In this malignancy, development of metastases is inevitable and is associated with increasing baseline prostate-specific antigen (PSA) levels. mCRPC has a median survival of approximately 3 years, and the hope is that delaying time to metastases will result in a delay of cancer-related morbidity and prolonged survival.
The PROSPER trial included 1,401 patients randomly assigned 2:1 to receive either enzalutamide 160 mg/day along with androgen-deprivation therapy (ADT; 933 patients) or placebo plus ADT (468 patients). The median age in the enzalutamide group was 74 years, and it was 73 years in the placebo group; median PSA doubling time in the two groups was 3.8 and 3.6 months, respectively. The primary outcome was MFS, defined as the time from randomization to radiographic progression or death within 112 days of treatment discontinuation.
The median MFS was 36.6 months with enzalutamide, compared with only 14.7 months with placebo (HR 0.29, 95% CI [0.24, 0.35]; p < 0.0001).
Of the 219 progression events in the enzalutamide group, 187 (85%) were radiographic, including 71 new bone metastases (32%), 109 new soft-tissue metastases (50%), and seven cases of concurrent new bone and soft-tissue metastases (3%). The other 32 events were death without documented progression (15%). Almost all the progression events with placebo (98%) were radiographic, with 79 new bone metastases (35%), 132 new soft-tissue metastases (58%), and 13 cases of concurrent new bone and soft-tissue metastases (6%). There were deaths without documented progression in the placebo group (2%).
A series of subgroup analyses showed that enzalutamide offered better outcomes than placebo in every group, including patients with longer and shorter PSA doubling times, patients from different geographic regions, ECOG performance status of 0 or 1 at baseline, and other subgroups.
The time to PSA progression was 37.2 months with enzalutamide, compared with only 3.9 months with placebo (HR 0.07, 95% CI [0.05, 0.08]; p < 0.0001). The time to first use of new antineoplastic therapy was also substantially longer with the study drug, at 39.6 months compared with 17.7 months for placebo (HR 0.21, 95% CI [0.17, 0.26]; p < 0.0001).
The median overall survival (OS) has not yet been reached in either group based on an interim analysis and longer follow-up is needed to determine whether enzalutamide affects OS in this setting. There was no statistically significant difference in survival at the time of this analysis, but early data shows a trend toward a reduction in the relative risk of death with enzalutamide, Dr. Hussain said.
In total, 87% of patients treated with enzalutamide and 77% of patients treated with placebo experienced an adverse event (AE) of any grade; 31% and 23%, respectively, had a grade 3 or higher AE. Grade 3 or higher AEs occurred in at least five patients in the enzalutamide group and included hypertension (5%), fatigue (3%), and hematuria (2%), among others at 1% or less. A total of 48 patients treated with enzalutamide (5%) had a major adverse cardiac event, compared with 13 patients treated with placebo (3%); 48 patients treated with enzalutamide also had memory impairment of any grade, compared with nine of patients treated with placebo.
Eric J. Small, MD, FASCO, Helen Diller Family Comprehensive Cancer Center and the University of California, San Francisco, presented results of the phase III SPARTAN trial, which compared the next-generation ASI apalutamide with placebo. A previously reported phase II study showed the agent resulted in greater than a 50% decline in PSA in 89% of patients with high-risk nmCRPC at 12 weeks.
“mCRPC is a uniformly fatal disease,” Dr. Small said. “Since it is well established that metastases are a major cause of morbidity and mortality […] the prevention of metastases represent an important unmet medical need.”
The study included 1,207 patients, randomly assigned 2:1 to receive either apalutamide 240 mg/day along with ADT (806 patients) or placebo plus ADT (401 patients). After MFS assessment, the study’s primary endpoint, patients could receive a second therapy at their physician’s discretion, including open-label abiraterone acetate plus prednisone; a second progression-free survival was measured after this subsequent therapy.
Patients were well matched between groups, with a median age of 74.0 years in both arms of the study, and a median time from initial diagnosis to randomization of just under 8 years.
The median MFS was 40.5 months with apalutamide, compared with 16.2 months with placebo (HR 0.28, 95% CI [0.23, 0.35]; p < 0.0001). Just as in the PROSPER trial, subgroup analysis showed the study drug benefited patients across all subgroups; the only exception was a nonsignificant trend toward benefit with apalutamide in black patients.
Based on the aggregate outcome data, the independent safety monitoring committee unanimously recommended the trial be unblinded, and the option be given to patients in the placebo arm to switch to apalutamide.
A secondary endpoint of time to metastasis was also significantly better with apalutamide, with a median of 40.5 months compared with 16.6 months with placebo (HR 0.27, 95% CI [0.22, 0.34]; p < 0.0001). The median PFS was 40.5 months with the study drug, compared with 14.7 months with placebo (HR 0.29, 95% CI [0.24, 0.36]; p < 0.0001).
The median time to symptomatic progression—defined as skeletal-related events, pain progression/worsening, or clinically significant symptoms—was not reached in either group, but it was better with apalutamide (HR 0.45, 95% CI [0.32, 0.63]; p < 0.0001). The median OS was not reached with apalutamide, and it was 39.0 months with placebo, which did not reach significance (HR 0.70, 95% CI [0.47, 1.04]; p = 0.07).
A total of 217 patients in the placebo arm went on to receive subsequent therapy for mCRPC, and 87% of those received an ASI; 68% of all patients treated with placebo who discontinued the study treatment went on to receive an ASI. The median second progression-free survival was not reached in the apalutamide group, and it was 39.0 months in the placebo arm (HR 0.49, 95% CI [0.36, 0.66]; p < 0.0001).
The median time to PSA progression with apalutamide was not reached, although it was 3.7 months with placebo (HR 0.06, 95% CI [0.05, 0.08]; p < 0.0001). In total, 90% of patients treated with apalutamide had a PSA decline of at least 50%, compared with only 2% of patients treated with placebo, for a relative risk of 40.09 (95% CI [21.0, 76.58]; p < 0.0001). Quality-of-life measures showed generally high scores similar to the general population in both groups.
In the apalutamide group, 45% of patients had a grade 3 or 4 AE, compared with 34% in the placebo group; 25% and 23%, respectively, had a serious AE, and 11% and 7%, respectively, had an AE leading to treatment discontinuation. AEs with apalutamide included rash (23.8% of patients), fall (15.6%), and fracture (11.7%).
Philip Kantoff, MD, of Memorial Sloan Kettering Cancer Center, discussed these two abstracts. He noted that although these were positive trials, there are still some caveats to use of these agents in the nmCRPC setting. “Treating asymptomatic patients carries a certain burden of proof, wherein benefit must clearly outweigh risk,” he said.
Based on available data, Dr. Kantoff said that it had not yet been clearly demonstrated that these agents provided a net benefit to patients. Specifically, no significant OS benefit has been demonstrated, nor an improvement in quality of life. Dr. Kantoff said that it is yet to be determined whether MFS is a valid surrogate endpoint for OS. He said the strongest evidence in favor of the therapies is the delay or reduction in skeletal events. There are also some increases in AEs, and, although they are low-frequency events, he noted that they are important to patients.
"My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how care patterns in these studies compare with actual practice,” Dr. Kantoff said.