Enzalutamide Improved Hormone-Sensative Prostate Ca Outcomes Regardless of Pretreatment PSA

Among patients with metastatic, hormone-sensitive prostate cancer, treatment with the oral androgen receptor inhibitor enzalutamide in addition to androgen deprivation therapy (ADT) was associated with improved clinical outcomes, regardless of baseline prostate-specific antigen (PSA) levels in a post hoc analysis of data from the ARCHES randomized, clinical trial.

Men treated with enzalutamide plus ADT following prior ADT had improved radiographic progression-free survival (rPFS) and overall survival compared to men not treated with the androgen receptor blocking drug.

PSA declining to undetectable levels (<0.2 ng/mL) was also associated with significantly better outcomes among enzalutamide-treated patients.

Findings from the post hoc analysis, published in JAMA Network Open, "highlight the utility of enzalutamide in the treatment of metastatic, hormone sensitive prostate cancer (mHSPC), irrespective of pre-treatment PSA level, and the clinical utility of PSA decline to undetectable in patients with mHSPC," wrote researcher Andrew J. Armstrong, MD, of the Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, North Carolina, and colleagues.

"Future studies should better characterize clinical and genetic factors associated with extraordinary response to enzalutamide plus ADT," the researchers noted. "In addition, further trials are recommended to test the value of further treatment intensification beyond doublet ADT plus androgen receptor pathway inhibitor therapy among those men who do not achieve undetectable PSA levels after treatment."

In the phase III ARCHES trial, treatment with enzalutamide was associated with delayed time to PSA progression (81.0%; P <.001), with roughly 68% of treated patients reaching undetectable PSA versus 17.6% receiving placebo.

Armstrong and colleagues noted that in men with mHSPC, baseline PSA level and PSA change from baseline to 12 weeks have been repeatedly shown to b, strong prognostic indicators of PSA progression.

"PSA declines are linked to improved survival across different treatment settings, including docetaxel, enzalutamide, or both, in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC)," they wrote. "Phase III clinical trials in men with mHSPC provided evidence supporting an association between PSA decline to undetectable levels (<0.2 or ≤0.2 ng/mL) and improved clinical outcomes."

Their goal in conducting the post hoc analysis was to examine "the association of treatment intensification with enzalutamide plus ADT versus ADT alone by PSA level at study enrollment in patients who received prior ADT and by depth of PSA reduction with clinical outcomes in men with mHSPC."

In the ARCHES trial, 1,150 patients (median age, 70 years; range, 46-92 years) were randomized 1:1 to treatment with enzalutamide (160 mg/d) plus ADT or placebo plus ADT, with all patients receiving ADT for 3 to 6 months before study enrollment was permitted.

"Radiographic progression-free survival and overall survival (OS) were correlated post hoc with PSA level at enrollment in patients with prior ADT and additionally with PSA decline at 6 months or undetectable PSA (<0.2 ng/mL) during study treatment," the researchers wrote.

Findings from the post hoc analysis showed:

• Improved rPFS and other outcomes associated with enzalutamide plus ADT treatment in men with PSA levels at enrollment of 0.2 to 4 ng/mL and above 4 ng/mL.
• Hazard ratios (HRs) for improved rPFS in men with PSA levels up to 0.2 ng/mL, above 0.2 to 4 ng/mL, and above 4 ng/mL were 0.59 (95% CI, 0.27-1.30), 0.32 (95% CI, 0.20-0.50), and 0.44 (95% CI, 0.32-0.62), respectively.
• Men who achieved undetectable PSA levels following treatment with enzalutamide plus ADT had an 86% reduced risk for radiographic disease progression (HR, 0.14 [95% CI, 0.09-0.23]; P <.001) and a 76% reduced risk of death (HR, 0.24 [95% CI, 0.17-0.34]; P < 0.001), compared to men in the same treatment group who did not achieve undetectable PSA levels.

A limitation of the post hoc analysis, cited by the researchers, was the small number of patients with PSA levels of up to 0.2 ng/mL at study enrollment, "which may have confounded the analysis of overall survival by enrollment PSA level."

"The small sample with PSA levels above 4 ng/mL may have affected clinical outcome findings in the enzalutamide plus ADT cohort," the researchers wrote. "Additionally, formal testing for the Cox proportional hazards assumption was not performed; therefore, those results should be interpreted cautiously."

This analysis was funded by Astellas Pharma Inc and Pfizer Inc, which co-developed enzalutamide. Armstrong reported receiving grants from Amgen, AstraZeneca, Bristol Myers Squibb, Janssen, and Merck as well as personal fees from AstraZeneca, Bayer, Myovant, and Novartis outside the submitted work. Other researchers reported receiving personal and/or other fees from Astrellas, Pfizer and/or other pharmaceutical companies during the conduct of the study.

Azad AA, et al "Enzalutamide and prostate-specific antigen levels in metastatic prostate cancer: a secondary analysis of the ARCHES randomized clinical trial" JAMA Netw Open 2025; DOI: 10.1001/jamanetworkopen.2025.8751.