Enzalutamide added to androgen deprivation therapy demonstrated a benefit in overall survival, radiographic progression-free survival, undetectable prostate-specific antigen rates, objective response rates, and other end points vs placebo/ADT in patients with metastatic hormone-sensitive prostate cancer regardless of whether or not they received prior local therapy.
Neal D. Shore, MD
Enzalutamide (Xtandi) added to androgen deprivation therapy (ADT) demonstrated a benefit in overall survival (OS), radiographic progression-free survival (rPFS), undetectable prostate-specific antigen (PSA) rates, objective response rates (ORRs), and other end points vs placebo/ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) regardless of whether or not they received prior local therapy.1 The data were from a post-hoc analysis of the phase 3 ARCHES trial (NCT02677896) that were presented during the 2022 AUA Annual Meeting.
Additionally, the improvements with enzalutamide, which were seen across all patient subgroups, also cascaded to symptomatic skeletal event (SSEs), new antineoplastic therapy, castration resistance, and deterioration of urinary symptoms vs placebo plus ADT.
For example, in patients who did receive prior local treatment, the median OS was not reached with enzalutamide/ADT (n = 131) nor placebo/ADT (n = 141) at a median follow-up of 44.6 months (HR, 0.56; 95% CI, 0.34-0.92; P = .02). In the subgroup of those who did not receive prior local treatment, the median OS was also not reached in both arms (HR, 0.68; 95% CI, 0.54-0.86; P = .001).
“This post-hoc analysis demonstrated the long-term survival benefit of enzalutamide plus ADT versus placebo plus ADT in patients with mHSPC who received prior local therapy, supporting the utility of enzalutamide irrespective of receipt of local therapy,” lead study author Neal D. Shore, MD, director of CPI, of Carolina Urologic Research Center, and coinvestigators, wrote in a poster presented during the meeting. “These results are consistent with those previously reported in the overall population of ARCHES.”
In December 2019, the FDA approved enzalutamide for use in combination with ADT for the treatment of patients with mHSPC.2 The decision was based on earlier findings of the ARCHES trial, in which 1150 patients were randomized 1:1 to receive enzalutamide at 160 mg daily plus ADT or placebo plus ADT. Stratification factors included disease volume and prior docetaxel use.
Results showed that the enzalutamide arm significantly improved rPFS and OS, as well as key secondary end points, vs placebo/ADT in this patient population.3 A long-term OS benefit was also reported in a subsequent analysis.4
ARCHES was unblinded after the primary analysis to permit patients who were randomized to placebo/ADT to cross over to enzalutamide/ADT in an open-label extension phase of the research.
In the post-hoc analysis of ARCHES, investigators sought to explore the effect of enzalutamide plus ADT compared with placebo/ADT on the OS of patients who received prior local treatment to the prostate. To be eligible for this analysis, patients must have received local therapy, which was defined as prior radical prostatectomy (RP) and/or radiation (RT) to the prostate in the definitive, adjuvant, or salvage setting.
Enrollment was based on investigator-assessed metastases. Following study entry, metastases were examined by a blinded independent central review. Moreover, prior ADT and up to 6 cycles of prior docetaxel were allowed. Those with disease progression prior to randomization while receiving ADT and/or docetaxel were excluded.
The overall ARCHES population included 1150 patients with mHSPC. Of these patients, 272 had received prior local therapy; 131 patients were on the enzalutamide arm and had received radical prostatectomy (n = 37), radiation (n = 59), or both (n = 35) and 141 patients were on the placebo arm who were previously given RP (n = 45), RT (n = 52), or both (n = 44).
A total 184 patients (31.9%) who were randomized to placebo/ADT remained progression free and gave informed consent crossed over following unblinding of the study. Of these, 180 patients received enzalutamide/ADT. The median time to crossover was 21.5 months.
Baseline characteristics were mostly similar between the 2 groups. However, at study enrollment, a greater proportion of patients who did not receive local treatment had distant metastatic disease (M1) at initial diagnosis (enzalutamide/ADT arm, 84.7%; placebo/ADT, 78.6%) as well as an ECOG performance status of 1 (enzalutamide/ADT, 76.7%; placebo/ADT, 74.9%) and a Gleason score of 8 or higher (enzalutamide/ADT, 77.4%; placebo/ADT, 72.9%), vs those who did have local therapy.
Additional results showed that, in both patients with and without prior local therapy, rPFS was improved with enzalutamide/ADT (with prior treatment, HR, 0.44; without prior treatment, HR, 0.38), as well as time to PSA progression (HR, 0.34 and HR, 0.27, respectively), time to first SSE (HR, 0.39 and HR, 0.52), time to castration resistance (HR, 0.42 and HR, 0.39), time to new antineoplastic therapy (HR, 0.36 and HR, 0.40), time to deterioration of urinary symptoms (HR, 0.90 and HR, 0.88), and time to pain progression (HR, 0.88 and HR, 0.98).
Of patients who had detectable PSA at baseline, more patients treated with enzalutamide plus ADT achieved undetectable PSA (<0.2 ng/mL) compared with placebo plus ADT in both the prior treatment (84.5%) and no prior treatment. Moreover, there was a greater rate difference in those who had not received local treatment (rate difference [RD], 56.9%; 95% CI, 51.5-62.3; P <.0001) compared with those who had received it (RD, 39.2%; 95% CI 27.3-51.0; P <.0001).
ORRs were also higher in the enzalutamide/ADT arm compared with placebo/ADT in both subgroups. Enzalutamide/ADT elicited a 72.4% ORR in patients with prior treatment and 83.2% in those without; these rates were 59.2% and 61.4%, respectively, with placebo/ADT.
Investigators also noted that there were no safety differences between the prior local therapy and no prior local treatment subgroups, and that the safety profiles were comparable to what had been observed in the overall study population.