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Results shared at the AAU 2021 annual meeting showed that prior antiandrogen therapy had no impact on the effectiveness of adding enzalutamide to androgen deprivation therapy (ADT) in patients with ADT. ‘hormone-sensitive metastatic prostate cancer (mHSPC).1
Results of a post hoc analysis of the ARCHES phase 3 trial showed that adding enzalutamide to ADT reduced the risk of radiographic progression or death by 61% (95% CI, 0, 30-0.50) compared to ADT alone in the general 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 did not.
Notably, these results were maintained in a sensitivity analysis of the gonadotropin releasing agent (GnRHa), which monitored for potential confounding effects of GnRH antagonists and bilateral orchiectomies.
“The HR observed for the previous antiandrogen subgroups were comparable to those [observed in] the overall population of the original ARCHES primary scan of all endpoints, ”said lead study author Neal Shore, MD, FACS, medical director of the Carolina Urologic Research Center, during an oral presentation on the data.
Enzalutamide is approved for use in patients with castration-resistant prostate cancer in several countries, as well as those with mHSPC. Establishment of the agent’s efficacy in people with metastatic hormone-sensitive disease was based on the results of the ARCHES trial, as well as the phase 3 ENZAMET trial (NCT02446405), which both demonstrated superior clinical results with enzalutamide.
Patients with mHSPC often receive short-term first generation antiandrogen therapy to prevent or block testosterone surges and symptomatic progression by the time ADT is started. However, the impact of previous antiandrogen therapy on outcome with enzalutamide is largely unknown.
For this reason, the investigators conducted an analysis of the population enrolled in the ARCHES trial, as the study eligibility criteria permitted prior antiandrogen therapy. The objective of the analysis was to determine the impact of previous antiandrogen therapy on the efficacy of enzalutamide plus ADT compared to placebo plus ADT in patients with mHSPC. Previous treatment could include short-term use, defined as 4-6 week exposure, and longer-term use.
In total, the ARCHES study included a total of 1150 patients who were randomized 1: 1 to receive either enzalutamide at a dose of 160 mg per day plus ADT or ADT alone. The primary endpoint 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 index of 0 or 1. Patients were stratified by disease volume (low vs. high) and treatment. previous docetaxel (0 vs. 1 to 5 vs. 6. Criteria for discontinuation of the study included radiographic progression, unacceptable toxicity, or initiation of an investigational agent or new treatment for cancer of the prostate.
For post-hoc analysis, prior antiandrogen therapy was allowed if given at the same time as less than 6 months of ADT, using luteinizing hormone release agonists / antagonists or bilateral orchiectomy prior to on day 1.
Populations examined in the study included those in the general population who had or not received prior antiandrogen therapy, those who received GnRH analogues with or without prior antiandrogen therapy, and those who received prior antiandrogen therapy for 1 month. or less or more than 1 month. month.
The primary endpoint of the analyzes was rPFS. Primary secondary endpoints included time to prostate specific antigen (PSA) progression, time to initiation of new antineoplastic therapy, time to resistance to castration , undetectable PSA level 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 previous antiandrogen therapy (n = 205 with enzalutamide / ADT and n = 230 with ADT alone), the median age in the arms was 69.5 years, 78.5% had an ECOG performance index of 0.62% had a high disease volume, and 69% had a Gleason score of 8 or greater at initial diagnosis. Sixty-eight percent of patients had distant metastases at initial diagnosis, the median PSA at entry into the study was 3.33 µg / L. In addition, 22% of patients have received docetaxel in the past. Regarding ADT, 91.5% of patients received GnRHa, 5.5% received a GnRH antagonist and 1% received bilateral orchiectomy.
Among those who had not previously received antiandrogenic agents (n = 369 with enzalutamide / ADT and n = 346 with ADT alone), the median age in the arms was 69.5 years, 77% had an ECOG performance index of 0.64% had disease volume, 64.5% had a Gleason score of 8 or greater at diagnosis, and 65.5% had distant metastases at initial diagnosis. In addition, the median PSA at entry into the study was 6.65 µg / L. Fifteen percent of patients have received docetaxel previously. Additionally, 42% had GnRHa, 34.5% had a GnRH antagonist, and 9.5% had bilateral orchiectomy.
Additional data showed that the HR for time to PSA progression in the prior antiandrogen treatment group was 0.13 (95% CI, 0.07-0.025) versus 0.22 (95% CI %, 0.15 to 0.32) in the group without prior antiandrogen treatment. Thus, the effect of treatment with enzalutamide / ADT on the time to progression of PSA was maintained compared to ADT alone; this was true regardless of previous antiandrogen therapy, duration of antiandrogen use, or GnRH analog administration.
Regarding the time to new antineoplastic therapy, the RR was 0.19 (95% CI, 0.10-0.036) in the prior antiandrogen treatment group versus 0.37 (95% CI, 0.25-0.56) in the group without prior antiandrogen treatment. Again, the effect of enzalutamide / ADT on the time to re-antineoplastic therapy was maintained compared to ADT alone.
In terms of time to resistance to castration, the RR was 0.28 (95% CI, 0.19-0.41) in the group that received prior antiandrogen therapy versus 0.29 (CI of 95%, 0.21-0.39) in the group without previous antiandrogen treatment. Regarding the time to the first SES, the RR was 0.55 (95% CI, 0.28-1.1) in the group having received prior antiandrogen therapy versus 0.51 (95% CI , 0.29-0.89) in the group without previous antiandrogen treatment.
The difference in undetectable PSA levels between the study arms was 50.3% (95% CI, 41.5% to 59.1%) for those who had previous antiandrogen therapy versus 51.4% (95% CI, 44.9 to 57.9%) for those who had never received antiandrogen therapy. . Enzalutamide plus ADT increased the proportion of patients with an objective response in the treatment subsets. The difference in TRG was 22.6% (95% CI, 7.2% to 38.1%) versus 20.5% (95% CI, 9.4 to 31.6%) in the 2 groups , respectively.
In terms of safety, the most frequently reported adverse reactions included musculoskeletal events, fatigue and hypertension, and no significant difference in the safety profile of enzalutamide plus ADT over previous antiandrogen therapy was observed. observed.
Reference
1. Shore N, Iguchi T, Villers A, et al. Enzalutamide in patients with metastatic hormone-sensitive prostate cancer who received prior antiandrogen therapy: ARCHES post hoc analysis. Presented at the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD34-07.
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