Enzalutamide Plus ADT Improves rPFS, OS in Metastatic HSPC With Prior ADT

Enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) elicited significant improvements in radiographic progression-free survival (rPFS) and overall survival (OS) vs placebo in patients with metastatic hormone-sensitive prostate cancer (HSPC), according to post-hoc analyses from the phase 3 ARCHES trial (NCT02677896) presented at the 2022 ESMO Congress.¹

The combination improved rPFS vs placebo across patients who had received prior ADT in all baseline prostate-specific antigen (PSA) value subgroups, including patients with PSA levels at or below 0.2 μg/L (hazard ratio [HR], 0.60; 95% CI, 0.27-1.33), above 0.2 to 4 μg/L (HR, 0.32; 95% CI, 0.20-0.50), and above 4 μg/L (HR, 0.45; 95% CI, 0.32-0.63).

The small sample size in the group with levels at or below 0.2 μg/L likely contributed to the upper bound of the 95% CI crossing 1. When adjusted for the crossover, the rPFS benefit with the oral androgen receptor inhibitor enzalutamide was more pronounced across all baseline PSA subgroups. Specifically, the HRs were 0.33 (95% CI, 0.10-0.67), 0.47 (95% CI, 0.30-0.69), and 0.69 (95% CI, 0.51-0.90) in the groups with PSA levels at or below 0.2 μg/L, above 0.2 to 4 μg/L, and above 4 μg/L, respectively.

Baseline increases in PSA values independently predict PSA progression in metastatic HSPC. In the ARCHES trial, more than 90% of patients had received prior ADT and had baseline PSA levels ranging from under 0.2 μg/L to more than 4 μg/L before study randomization. The overall median baseline PSA level was 5.21 μg/L, with a similarly decreased risk of radiographic progression observed with enzalutamide plus ADT vs placebo plus ADT in patients with baseline PSA levels greater than (HR, 0.41; 95% CI, 0.30-0.58) or less than (HR, 0.38; 95% CI, 0.26-0.54) the median. Baseline PSA was defined as PSA value prior to randomization to enzalutamide or placebo.

In previous post-hoc analyses of the ARCHES trial, enzalutamide plus ADT elicited a clinical benefit over placebo plus ADT for end points including rPFS, time to PSA progression, and time to castration resistance, regardless of baseline PSA level.

The ARCHES trial enrolled 1150 patients with metastatic HSPC who were randomly assigned 1:1 to ADT plus enzalutamide at 160 mg per day or placebo. Patients were stratified by prior docetaxel use and disease volume at enrollment. Patients were permitted to have prior treatment with ADT and up to 6 cycles of docetaxel before baseline PSA assessment and initiation of study treatment.

Patients were excluded if they had received over 3 months of ADT or over 6 months of ADT plus prior docetaxel.

The trial was unblinded after the primary analysis, allowing 31.3% (n = 180) of patients who were assigned to the placebo arm to cross over to the enzalutamide arm in an open-label extension. The median time to crossover of 21.5 months.

Investigators conducted post-hoc analyses of the primary end point, rPFS, and the secondary end points OS, time to PSA progression, and time to castration resistance to determine the efficacy of enzalutamide plus ADT in patients whose PSA levels declined to low levels following prior ADT use.

Radiographic imaging was performed at screening, week 13, and every 12 weeks thereafter. PSA levels were measured at screening, weeks 1, 5, and 13, and every 12 weeks thereafter. Investigators conducted a final measurement 30 days after the last dose of study drug or before the start of a new antineoplastic therapy, whichever occurred first.

In total, 90% of patients in the ARCHES population had received prior ADT and 18% received prior docetaxel. The median duration of prior ADT use was 1.6 months (range, 0.03-55.3) for the enzalutamide arm and 1.6 months (range, 0.03-198.8) for the placebo arm.

A total of 1047 patients who had prior ADT had available baseline PSA values. Of these, 12.8% (n = 134) had baseline PSA levels at or below 0.2 μg/L and 35.5% (n = 372) had baseline PSA levels above 0.2 to 4 μg/L. Most patients (51.7%; n = 541) had baseline PSA levels above 4 μg/L.

Baseline characteristics were similar between the treatment groups in each PSA category. Among patients with baseline PSA levels at or below 0.2 μg/L, 30.6% (n = 19) had an ECOG performance status of 1 compared with 18.1% (n = 13) in the placebo arm.

The proportion of patients with baseline PSA levels above 0.2 to 4 μg/L and an ECOG performance status of 1, high-volume disease, or a total Gleason score of 8 or higher was lower in the enzalutamide arm vs the placebo arm. Specifically, 17.3% (n = 33) of the patients in this PSA group treated with enzalutamide had an ECOG performance status of 1 vs 21.5% (n = 39) of those who received placebo. A total of 52.9% (n = 101) of patients in this PSA group treated with enzalutamide had high-volume disease compared with 62.4% (n = 113) of those who received placebo.

Regarding total Gleason score at diagnosis, 61.3% (n = 117) of patients in this PSA group treated with enzalutamide and 66.9% (n = 121) of those who received placebo had a score of 8 or higher. Additionally, 69.1% (n = 132) patients in this PSA group in the enzalutamide arm had distant metastases at diagnosis vs 64.6% (n = 117) of those in the placebo arm.

Among patients with PSA levels above 4 μg/L, 73.6% (n = 206) of the patients in the enzalutamide arm had a total Gleason score of 8 or higher vs 64.4% (n = 168) of patients in the placebo arm. Moreover, 77.5% (n = 217) of the patients who received enzalutamide had distant metastases at diagnosis compared with 69.3% (n = 181) of those who received placebo.

Enzalutamide plus ADT trended toward improved OS vs placebo plus ADT in all PSA subgroups. Specifically, the HRs were 0.58 (95% CI, 0.27-1.24), 0.56 (95% CI, 0.38-0.82), and 0.75 (95% CI, 0.56-1.00) in the groups with PSA levels at or below 0.2 μg/L, above 0.2 to 4 μg/L, and above 4 μg/L, respectively.

When adjusted for the 95% CI crossover seen in the group with PSA levels at or below 0.2 μg/L, OS improvement with enzalutamide plus ADT with prior ADT use was observed in the groups with baseline PSA levels between 0.2 and 4 μg/L (HR, 0.54; 95% CI, 0.33-0.80) and above 4 μg/L (HR, 0.65; 95% CI, 0.47-0.86). Additionally, investigators noticed a trend in OS improvement in patients with PSA levels at or below 0.2 μg/L (HR, 0.48; 95% CI, 0.18-1.08).

The enzalutamide arm also experienced a reduced risk of PSA progression and castration resistance vs the placebo arm. Regarding time to PSA progression, the HRs were 0.25 (95% CI, 0.09-0.69), 0.28 (95% CI, 0.19-0.42), and 0.27 (95% CI, 0.21-0.37) in the groups with PSA levels at or below 0.2 μg/L, above 0.2 to 4 μg/L, and above 4 μg/L, respectively. Regarding time to castration resistance, the HRs were 0.44 (95% CI, 0.24-0.81), 0.40 (95% CI, 0.29-0.55), and 0.36 (95% CI, 0.28-0.46) in the groups with PSA levels at or below 0.2 μg/L, above 0.2 to 4 μg/L, and above 4 μg/L, respectively.

Moreover, interaction tests determined that baseline PSA category had no effect on time to PSA progression (P = .967) or time to castration resistance (P = .560). These findings regarding overall time to PSA progression and overall time to castration resistance were maintained when adjusted for crossover, with HRs of 0.19 (95% CI, 0.14-0.25; P < .001) and 0.31 (95% CI, 0.24-0.39; P < .001), respectively.

During the treatment period, 88.5% (n = 169) of the patients who received enzalutamide and 22.0% (n = 26) of those who received placebo in the group with a baseline PSA level above 0.2 to 4 μg/L achieved undetectable PSA levels, defined as levels at or below 0.2 μg/L. Additionally, 83.8% (n = 67) of the patients in this group who crossed over from placebo to enzalutamide reached undetectable PSA levels.

In the group with baseline PSA levels above 4 μg/L, 62.5% (n = 175) of the enzalutamide arm and 4.3% (n = 8) of the placebo arm achieved undetectable PSA levels. A total of 37.8% (n = 17) of the patients in this group who crossed over from placebo to enzalutamide also reached undetectable PSA levels.

Reference

Petrylak DP, Azad AA, Szmulewitz RZ, et al. Overall survival in patients with metastatic hormone-sensitive prostate cancer who received prior androgen deprivation therapy and reached low prostate-specific antigen levels treater further with enzalutamide: post hoc analyses of ARCHES. Ann Oncol. 2022;33(suppl 7):S1183-S1184. doi:10.1016/j.annonc.2022.07.1884