Results from a phase 3 study show that the continuous maintenance therapy of enzalutamide reduces the risk of disease progression in certain patients with metastatic castration resistant prostate cancer.
The continuation of enzalutamide (Xtandi) maintenance therapy for patients with metastatic castration resistant prostate cancer (mCRPC) on docetaxel plus androgen deprivation therapy delayed the time to progression of disease when compared with placebo, according to results published in The Lancet Oncology.1
Findings from the 2-period, multinational, double-blind, randomized, placebo-controlled, phase 3b PRESIDE study (NCT02288247) showed that in the 136 patients given 160 mg of enzalutamide plus 75 mg/m2 of docetaxel and 10 mg of prednisone they had a significant improvement to the risk of their progression compared with 135 on placebo and the same amount of docetaxel and prednisone.
The median progression-free survival (PFS) was 9.5 months (95% CI, 8.3-10.9) in the enzalutamide group in comparison to 8.3 months (95% CI, 6.3-8.7) in the placebo group (HR 0.72; 95% CI 0·53–0·96, P = 0.027). Moreover, 74% (n = 93) of patients in the enzalutamide group experienced overall disease progression compared to 76% of patients in the placebo group. Enzalutamide was also favored vs placebo in patients who also had progression of bone disease and soft tissue disease at 26% vs 27% and 26% vs 33%, respectively. However, more patients had unequivocal clinical progression on enzalutamide, 14%, compared with patients on placebo, 10%, who progressed.
“PRESIDE provides evidence that concomitant administration of enzalutamide and docetaxel might serve as a treatment option for patients who progress on enzalutamide alone,” explained researchers in their assessment of the results.
Ultimately, 271 patients with mCRPC were randomized to either enzalutamide maintenance plus chemotherapy or placebo. Eligible patients had to have histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features, and serum testosterone concentrations of 1.73 nmol/L or less. These patients also had to have progressed while being treated with androgen deprivation therapy with a luteinising hormone-releasing hormone agonist, antagonist, or after bilateral orchiectomy.
Progression at study entry was defined as either three observed increases in prostate-specific antigen (PSA) concentrations, with 1 week or more between each increase, or a PSA value of 2 ng/mL or greater. Patients were considered to have metastatic disease if at least two bone lesions (assessed by a bone scan) or soft tissue disease (assessed by CT or MRI) were documented. Exclusion criteria included if patients previously used aminoglutethimide, ketoconazole, abiraterone acetate, enzalutamide, or cytotoxic chemotherapy, antiandrogens, 5-α reductase inhibitors, oestrogens, or opiate analgesia 4 weeks before the initiation of enzalutamide.
136 patients were then assigned to enzalutamide and 135 were assigned to placebo with the median age of patients in the treatment arm were 71 years of age and 69 years of age in the placebo arm. In the study arm, 50% of patients had an ECOG performance score of 1 with 50% in the placebo arm having an ECOG score of 0. At diagnosis 56% of patients in the enzalutamide arm had a Gleason score of 8 or higher compared with 57% in the placebo arm. Location of the metastases were either in the bone, soft tissue, or bone and soft tissue in the study arm and placebo arm at 42% vs 35%, 21% vs 18%, and 37% vs 47%, respectively.
The responses for this patient group were favored by patients with enzalutamide, and more so in the overall response rate (ORR) of patients with soft tissue disease at 41% compared with 39% in the placebo group. Enzalutamide was also associated with a significant reduction in risk of PSA progression (HR 0.58; 95% CI, 0.41–0.82, P = 0.0021). Moreover, in the enzalutamide group median time to PSA progression was 8.4 months (95% CI, 8.2–9.0) compared with 6.2 months (95% CI, 5.4–8.3) in the placebo group.
“Although the enzalutamide group of PRESIDE had higher levels of serious treatment-emergent adverse events than the placebo group, the overall safety findings of the trial are consistent with those of previous studies,” the researchers noted when looking at the adverse events (AEs) associated with enzalutamide while noting its efficacy in this patient population.
Overall, each study arm had similar total incidences of grade 3 treatment-emergent AEs (TEAEs) at 38% in the enzalutamide arm and 37% in the placebo group, with 24% of patients in the study arm experiencing a grade 4 TEAE compared with 25% in the placebo group. The most common TEAEs in the enzalutamide arm vs placebo arm included neutropenia (13% vs 9%), asthenia (7% vs 4%) and the most common grade 4 TEAE was neutropenia (17% vs 21%). Other notable TEAEs at grades 1-2 in the enzalutamide arm vs placebo arm also included alopecia (30% vs 27%), fatigue (27% vs 18%), and docetaxel related TEAEs (32% vs 36%).
Merseburger AS, Attard G, Åström L, et al. Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study. Lancet Oncol. 2022 Nov;23(11):1398-1408. doi: 10.1016/S1470-2045(22)00560-5