In a subgroup analysis of the phase 3 EMBARK study, enzalutamide alone or with leuprolide acetate improved metastatic-free survival in men with high-risk prostate cancer following radiotherapy.
Enzalutamide (Xtandi), when administered as monotherapy or in combination with leuprolide acetate (Eligard), yielded clinically meaningful improvement in metastatic-free survival (MFS) compared with leuprolide acetate alone in men with high-risk prostate cancer following radiotherapy, according to findings from a subgroup analysis of the phase 3 EMBARK study (NCT02319837). Results were presented at the 2023 American Society for Radiation Oncology (ASTRO) Annual Meeting.1
In the combination arm (n = 265), investigators reported 37 events (14%) with a median MFS that was not reached (NR). In the leuprolide-only arm (n = 283), there were 76 events (27%) and a median MFS of 85.1 months (HR, 0.45; 95% CI, 0.300.66; P < .0001).
Similarly, MFS for enzalutamide monotherapy was not reached compared with the median of 85.1 months for the leuprolide-only arm (95% CI, 80.1-NR). The HR was 0.57 (95% CI, 0.390.82; P = .0025).
“In patients with high-risk biochemical relapse and prior radiotherapy, both enzalutamide in combination with leuprolide and enzalutamide monotherapy demonstrated a clinically meaningful improvement in metastasis-free survival in comparison [with] leuprolide alone in patients with prior radiotherapy,” lead author Swetha Sridharan, MBBS, a radiation oncologist and conjoint lecturer at the University of Newcastle and Calvary Mater Newcastle in New South Wales, Australia, said during the presentation.
The primary analysis showed that after a median follow-up of 60.7 months, MFS in both the combination (HR, 0.42; 95% CI, 0.30-0.61; P < .0001) and the enzalutamide monotherapy (HR, 0.63; 95% CI, 0.46-0.87; P = .0049) was clinically meaningful and statistically superior to leuprolide acetate.2
A total of 1068 patients were randomly assigned to 3 arms: enzalutamide (160 mg) plus leuprolide acetate (22.5 mg); placebo plus leuprolide acetate; and enzalutamide monotherapy (160 mg). Patients were stratified by screening prostate- specific antigen (PSA) between 10 ng/mL or less vs higher than 10 ng/mL, prior hormonal therapy, and PSA doubling time of 3 months or less vs greater than 3 to 9 months.
At week 36 if the PSA was less than 0.2 ng/mL, treatment was suspended at week 37. PSA was monitored and treatment was reinitiated if levels began to rise. If PSA was higher than 0.2 ng/mL, patients would remain on treatment.
The primary end point was MFS by blinded independent central review (BICR) in enzalutamide plus leuprolide vs leuprolide alone. Secondary end points were MFS by BICR in enzalutamide monotherapy vs leuprolide acetate alone, time to PSA progression, and safety. The enzalutamide combination and leuprolide acetate arms were blinded, but the enzalutamide monotherapy arm was open label, according to the investigators.
The majority of patients received prior radiotherapy and had undergone radical prostatectomy. Specifically, 74.6%, 79.1%, and 72.1% of patients in the enzalutamide combination arm (n = 355), leuprolide acetate (n = 358), and enzalutamide monotherapy (n = 355) arms, respectively, had received prior radiotherapy. A total of 67.5%, 63.3%, and 64.8% of patients had received prior radiotherapy and undergone radical prostatectomy, respectively.
“Looking at the type of prior radiotherapy, unsurprisingly, most patients had external beam radiation treatment, with only a few having had brachytherapy,” Sridharan said. “The treatment fields were confined to the primary and pelvis.”
Demographic characteristics showed that across all arms the median age of patients was 69 years (range, 51-84), 70 years (range, 50-87), and 70 (range, 50-93) in the enzalutamide combination, leuprolide acetate, and enzalutamide monotherapy arms, respectively.
Most participants were White, and investigators reported a small minority of other races. More than 80% (82.3%) of patients had a screening PSA doubling time in the range of greater than 3 but less than 9 months. Most patients at the time of randomization had a PSA of less than 10.
Sridharan said that within 10 years following definitive therapy for prostate cancer, approximately 20% to 50% of patients experience disease recurrence characterized by rising PSA levels.3 In addition, patients with high-risk biochemical recurrence are at increased risk of prostate cancer– specific mortality.4
Sridharan said that the results must be interpreted with caution because of the low number of events. “One of the limitations of the study is that high-risk biochemical recurrence was based on PSA-doubling time and not prior therapies,” Sridharan said. “As a result, baseline data on prior therapies is limited. Despite this, we believe that the data support enzalutamide, [an androgen receptor inhibitor] in combination with androgen deprivation therapy. If approved in this setting, the regimen has the potential to become a new standard of care for patients with high-risk biochemical relapse following radiotherapy.”