Efficacy of enzalutamide in mHSPC unaffected by prior ADT

Findings shared during the 2021 AUA Annual Meeting showed that prior antiandrogen therapy had no impact on the efficacy of adding enzalutamide to androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).1

Results from a posthoc analysis of the phase 3 ARCHES trial showed that the addition of enzalutamide to ADT reduced the risk of radiographic progression or death by 61% (95% CI, 0.30-0.50) vs ADT alone in the overall patient population. The hazard ratio (HR) for radiographic progression-free survival (rPFS) was 0.39 (95% CI, 0.26-0.59) in those who had received prior antiandrogen therapy, and 0.39 (95% CI, 0.29-0.54) in those who had not.

Notably, these results were maintained in a gonadotropin-releasing hormone agonist (GnRHa) sensitivity analysis, which controlled for potential confounding effects of GnRH antagonists and bilateral orchiectomies.

“Observed HRs for the prior antiandrogen subgroups were comparable to those [observed in] the overall population from the original ARCHES primary analysis of all end points,” lead study author Neal Shore, MD, FACS, medical director of the Carolina Urologic Research Center, said during an oral presentation on the data.

Enzalutamide is approved for use in patients with castration-resistant prostate cancer in multiple countries, and well as for those with mHSPC. The establishment the agent’s efficacy in those with metastatic hormone-sensitive disease was based on results from the ARCHES trial, as well as the phase 3 ENZAMET trial (NCT02446405), both of which demonstrated superior clinical outcomes with enzalutamide.

Patients with mHSPC often receive short-term first-generation antiandrogen treatment to prevent or block testosterone flares and symptomatic progression at the time that ADT is started. However, the impact of prior antiandrogen treatment on outcomes with enzalutamide is largely unknown.

Due to this, investigators conducted an analysis of the population enrolled to the ARCHES trial, as the study’s eligibility criteria permitted prior antiandrogen therapy. The objective of the analysis was to determine the impact of prior antiandrogen therapy on the efficacy of enzalutamide plus ADT vs placebo plus ADT in patients with mHSPC. Prior therapy could include short-term use, defined as 4 to 6 weeks of exposure, and longer-duration use.

In total, the ARCHES study enrolled a total of 1150 patients who were randomized 1:1 to receive either enzalutamide at dose of 160 mg daily plus ADT, or ADT alone. The primary end point of the study was rPFS.

To be eligible for enrollment, patients had to have a confirmed diagnosis of mHSPC, histologically confirmed adenocarcinoma, and an ECOG performance status of 0 or 1. Patients were stratified by volume of disease (low vs high) and prior docetaxel therapy (0 vs 1 to 5 vs 6 cycles. Discontinuation criteria for the study included radiographic progression, unacceptable toxicity, or initiation of an investigational agent or new therapy for prostate cancer.

For the post-hoc analysis, prior antiandrogen treatment was allowed if it was given concurrently with less than 6 months of ADT, using luteinizing hormone–releasing agonists/antagonists or bilateral orchiectomy before day 1.

The populations examined on the study included those in the overall population who did or did not receive prior antiandrogen therapy, those who received GnRH analogs with or without prior antiandrogen therapy, and those who received prior antiandrogen therapy for 1 month or less or more than 1 month.

The primary end point of the analyses was rPFS. Key secondary end points included time to prostate-specific antigen (PSA) progression, time to initiation of new antineoplastic therapy, time to castration resistance, PSA undetectable rate defined as PSA less than 0.2 ng/mL, time to first symptomatic skeletal event (SSE), overall response rate (ORR), and safety.

Among those who received prior antiandrogen therapy (n = 205 with enzalutamide/ADT and n = 230 with ADT alone), the median age across the arms was 69.5 years, 78.5% had an ECOG performance status of 0, 62% had high disease volume, and 69% had a Gleason score of 8 or higher at initial diagnosis. Sixty-eight percent of patients had distant metastasis at initial diagnosis, the median PSA at study entry was 3.33µg/L. Moreover, 22% of patients previously received docetaxel. Regarding ADT, 91.5% of patients received a GnRHa, 5.5% received a GnRH antagonist, and 1% received a bilateral orchiectomy.

Among those who did not previously receive antiandrogen agents (n = 369 with enzalutamide/ADT and n = 346 with ADT alone), the median age across the arms was 69.5 years, 77% had an ECOG performance status of 0, 64% had high disease volume, 64.5% had a Gleason score of 8 or higher at diagnosis, and 65.5% had distant metastasis at initial diagnosis. Moreover, the median PSA at study entry was 6.65 µg/L. Fifteen percent of patients received prior docetaxel. Moreover, 42% had a GnRHa, 34.5% had a GnRH antagonist, and 9.5% had a bilateral orchiectomy.

Additional data showed that the HR for time to PSA progression in the prior antiandrogen therapy group was 0.13 (95% CI, 0.07-0.025) vs 0.22 (95% CI, 0.15-0.32) in the no prior antiandrogen therapy group. As such, the treatment effect of enzalutamide/ADT on time to PSA progression was maintained vs ADT alone; this was true, irrespective of prior antiandrogen therapy, duration of antiandrogen use, or administration of GnRH analogs.

Regarding the time to new antineoplastic therapy, the HR was 0.19 (95% CI, 0.10-0.036) in the prior antiandrogen therapy group vs 0.37 (95% CI, 0.25-0.56) in the no prior antiandrogen therapy group. Again, the effect of enzalutamide/ADT on time to new antineoplastic therapy was maintained versus ADT alone.

In terms of time to castration resistance, the HR was 0.28 (95% CI, 0.19-0.41) in the prior antiandrogen therapy group vs 0.29 (95% CI, 0.21-0.39) in the no prior antiandrogen therapy group. Regarding the time to first SSE, the HR was 0.55 (95% CI, 0.28-1.11) in the prior antiandrogen therapy group vs 0.51 (95% CI, 0.29-0.89) in the no prior antiandrogen therapy group.

The PSA undetectable rate difference among the study arms was 50.3% (95% CI, 41.5%-59.1%) for those with prior antiandrogen therapy vs 51.4% (95% CI, 44.9%-57.9%) in those with no prior antiandrogen therapy. Enzalutamide plus ADT increased the proportion of patients with an objective response across treatment subsets. The ORR difference was 22.6% (95% CI, 7.2%-38.1%) vs 20.5% (95% CI, 9.4%-31.6%) in the 2 groups, respectively.

In terms of safety, the most frequently reported adverse effects included musculoskeletal events, fatigue, and hypertension, and no significant differences in the safety profile of enzalutamide plus ADT by prior antiandrogen therapy were observed.


1. Shore N, Iguchi T, Villers A, et al. Enzalutamide in metastatic hormone-sensitive prostate cancer patients who received prior antiandrogen therapy: post hoc analysis of ARCHES. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD34-07.