Survival was increased with the treatment of enzalutamide plus standard of care compared with the use of other non-steroidal anti-androgens plus SOC for patients with metastatic hormone-sensitive prostate cancer. Results from an interim analysis of the phase III ENZAMET trial presented at the 2019 ASCO Annual Meeting showed that 80% of men with mHSPC were alive after 3 years with enzalutamide treatment compared with 72%.
Christopher J. Sweeney, MBBS
Survival was increased with the treatment of enzalutamide (Xtandi) plus standard of care (SOC) compared with the use of other non-steroidal anti-androgens (NSAAs) plus SOC for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Results from an interim analysis of the phase III ENZAMET trial presented at the 2019 ASCO Annual Meeting showed that 80% of men with mHSPC were alive after 3 years with enzalutamide treatment compared with 72%.
“Early enzalutamide substantially improved the time to progression and overall survival when added to standard metastatic hormone-sensitive therapy, the testosterone suppression alone or docetaxel,” said study co-chair Christopher Sweeney, MBBS, when presenting the findings. “The clinical interpretation is enzalutamide added to testosterone suppression represents an appropriate option for men with metastatic hormone-sensitive prostate cancer.”
ENZAMET was the first trial in men with mHSPC to report overall survival (OS) data for the use of enzalutamide and testosterone suppression, as well as outcomes if patients also received concurrent docetaxel.
The international, randomized phase III trial (NCT02446405) was led by the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. The trial enrolled 1125 men with mHSPC between March 2014 and March 2017. These men were randomized 1:1 to receive either enzalutamide or 1 of 3 first-generation NSAAs (bicalutamide [Casodex], nilutamide [Nilandron], or flutamide [Eulexin]) plus a testosterone-suppressing medicine. Less than half of the men (n = 503) received early doses of docetaxel. Patients were evaluated every 12 weeks and at progression could receive therapy for castration-resistant prostate cancer at the investigator’s discretion.
Androgen deprivation therapy (ADT) was allowed in the study up to 120 days prior to randomization, but intermittent ADT dosing was not allowed.
Randomization was stratified by volume of disease, planned early docetaxel use, planned anti-resorptive therapy, comorbidity score, performance status, and study site. A high volume of disease was considered the existence of visceral metastases and/or ≥4 bone metastases, with at least 1 of these beyond the pelvis and vertebral column.
The study authors noted that the 2 treatment arms were well balanced at baseline. The median age was 69 years across the 2 treatment arms.
As of the first interim analysis on February 28, 2019, when the criteria of 235 deaths had been met, patients had been followed for a median of 33 months. At 3 years, 64% of patients assigned to receive enzalutamide were still on the study treatment compared with 36% in the other NSAA arm. “We were told to report the results early because there was a survival benefit already seen after half of the information was received,” noted Sweeney, a medical oncologist at the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute.
The 3-year OS rate for men who received enzalutamide was 80% versus 72% in those who received another NSAA (HR, 0.67; 95% CI, 0.52-0.86;P= .002).
The time until clinical prostate-specific antigen (PSA) rise, clinical progression or death was significantly increased with enzalutamide compared to the other NSAAs (HR, 0.39; 95% CI, 0.33-0.47;P<.001). Looking only at clinical progression also showed a significant benefit with enzalutamide (HR, 0.40; 95% CI, 0.33-0.49;P<.001). “There was a 60% decreased rate of progression at any one time,” Sweeney commented.
Among men with a high volume of disease on imaging scans (n = 596), those who received enzalutamide had a 3-year OS rate of 71% compared with 63% with another NSAA (HR, 0.74; 95% CI, 0.55-1.01). The 3-year OS rates were 89% and 82% (HR, 0.48; 95% CI, 0.28-0.80), respectively, in men with a low volume of disease (n = 529).
In the subgroup of men who received planned concurrent docetaxel, the OS rates were similar regardless of treatment (HR, 0.90; 0.62-1.31). Of these patients, 71% had a high volume of disease. There was a more significant difference in survival in men who did not receive planned early docetaxel (HR, 0.53; 95% CI, 0.37-0.75). Only 37% of these patients had a high volume of disease.
Sweeney noted in a press release that docetaxel is not associated with a survival benefit in men with a low volume of disease, but improved survival was seen with enzalutamide.
Selected adverse events (AEs) were presented, including hypertension of grade 2 seen in 4% of those treated with another NSAA and in 8% treated with enzalutamide and of grade 3 in 5% versus 11%, respectively. Grade 2 (14% vs 25%) and grade 3 (1% vs 6%) fatigue, grade 2 (1% vs 5%) and grade 3 (<1% vs 1%) falls, grade 1/2 concentration impairment (1% vs 4%), syncope (1% vs 4%), and seizure (0% vs 1%) were also noted. The rate of selected AEs per year of treatment exposure was 34% (95% CI, 29%-40%) with enzalutamide compared with 33% (95% CI, 28%-39%) with other NSAAs.
Sweeney added in that enzalutamide actually increases docetaxel-related toxicity, which needed to be reconciled.
The study authors noted that enzalutamide appeared to be a more effective inhibitor of the androgen receptor than the standard NSAAs used in the trial as comparators; however, each led to different AEs. Going forward, the investigators plan to perform quality-of-life analyses as the data continue to emerge.
“In my view, using enzalutamide early on will allow our patients to avoid chemotherapy and steroids for many years, but hopefully improve their quality of life,” ASCO expert Neeraj Agarwal, MD, noted after the presentation. He said that the benefit seen in this study as well as in the TITAN trial with apalutamide (Erleada) were very encouraging, and suggested that targeting the androgen receptor may be the optimal approach for treating newly diagnosed patients with advanced prostate cancer.
Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial.J Clin Oncol. 2019;37(suppl; abstr LBA2).