Enzalutamide-ADT a win for biochemically recurrent prostate cancer

In the final overall survival (OS) analysis of the phase III EMBARK trial, the combination of enzalutamide and androgen deprivation therapy (ADT; leuprolide acetate) delivers a significant OS benefit in men with high-risk biochemically recurrent (hrBCR) prostate cancer without evidence of metastases on conventional imaging.

“There was a highly statistically significant and clinically meaningful survival benefit of over 40 percent when enzalutamide was added to ADT [vs ADT alone], with a hazard ratio (HR) of 0.597 [95 percent confidence interval {CI}, 0.444–0.804; p=0.0006],” said Dr Stephen Freedland from the Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, US, during his presentation at ESMO 2025.

“To our knowledge, this is the greatest survival benefit (based on HR) ever seen in a global phase III trial on prostate cancer – based on all study participants and not just in small subsets,” remarked Freedland amidst a round of applause.

There was also a very impressive 8-year OS rate in these high-risk patients of nearly 80 percent after a median follow-up of 94 months, he added. With ADT alone, the OS rate was 69.5 percent.

Moreover, every single subset of patients benefited from the enzalutamide and ADT combination regimen. “Although the numbers were small and did not always reach statistical significance, we could not identify any subset of patients who did not benefit from the addition of enzalutamide to ADT,” noted Freedland. The HRs ranged from 0.502 (geographic region – rest of the world) to 0.715 (geographic region – Europe).

Enzalutamide monotherapy also delivers benefit

There was a suggestion of OS benefit with enzalutamide monotherapy, with a 17 percent lower risk of death as opposed to leuprolide alone, but this fell short of statistical significance (HR, 0.830, 95 percent CI, 0.630–1.095; p=0.1867). The 8-year OS rates were 73.1 percent and 69.5 percent for the respective enzalutamide and leuprolide arms. [ESMO 2025, abstract LBA87]

Subgroup analysis also favoured enzalutamide monotherapy, but none of the subsets achieved statistical significance, Freedland noted. “Interestingly, among those with the worst disease (prostate-specific antigen [PSA] doubling time <3 months), the HR was 1.016, suggesting no benefit relative to an active control arm of ADT, whereas for those who were still high risk but slightly at the lower end of the spectrum (PSA doubling time >3 to ≤6 months), the HR was 0.796.”

Updated secondary outcomes

Both enzalutamide-based regimens significantly prolonged time-to-first use of new antineoplastic therapy (HR, 0.374, 95 percent CI, 0.287–0.489; p_nominal<0.0001 [combo] and HR, 0.570, 95 percent CI, 0.450–0.721; p_nominal<0.0001 [monotherapy]) and time-to-first symptomatic skeletal event (SSE; HR, 0.398, 95 percent CI, 0.221–0.716; p_nominal=0.0015 and HR, 0.493, 95 percent CI, 0.283–0.857; p_nominal=0.0105, respectively) compared with leuprolide monotherapy.

“Interestingly, there was a relatively similar [time-to-first SSE] benefit with enzalutamide monotherapy, [which could be due to] the lack of castration, leading to high testosterone and aromatization to oestrogen. This may have an additional bone health benefit,” Freedland explained.

Progression-free survival on first subsequent therapy was also statistically significant and clinically meaningful with enzalutamide – with (HR, 0.563, 95 percent CI, 0.420–0.755; p_nominal<0.0001) or without (HR, 0.761, 95 percent CI, 0.581–0.998; p_nominal=0.0465) leuprolide.

Safety profile

The safety findings also aligned with those reported in the primary analysis, noted Freedland. Across all three study arms, about half experienced grade ≥3 treatment-emergent adverse events (TEAEs), over 80 percent had TEAEs related to the study drug, and about 40 percent had serious TEAEs.

The rates of TEAEs leading to death were low (2.8, 1.4, and 3.4 percent for the respective combo regimen, leuprolide monotherapy, and enzalutamide monotherapy arms).

The rates of serious TEAEs related to the study drug were higher with enzalutamide (8.5 percent [combo] and 7.6 percent [monotherapy]) vs ADT alone (2.5 percent), but quality of life was preserved as previously reported, noted Freedland.

Importantly, there were no new safety signals with an additional 2.5 years of continued follow-up, he added.

Boosts initial findings

These results come on the heels of the initially reported EMBARK results, which showed a significant improvement in the primary endpoint of metastasis-free survival (MFS) with enzalutamide (vs leuprolide monotherapy) – be it alone (HR, 0.63, 95 percent CI, 0.46–0.87; p=0.005) or in combination with leuprolide (HR, 0.42, 95 percent CI, 0.30–0.61; p<0.001). OS data, which is a key alpha-protected secondary endpoint, were immature at the time of this analysis. [N Engl J Med 2023;389:1453-1465]

According to Freedland, the initial EMBARK findings have led to the approval of enzalutamide for hrBCR non-metastatic castration-sensitive prostate cancer in the US, EU, and several other countries, as well as inclusion in guidelines.

The EMBARK population comprised 1,068 men with hrBCR prostate cancer, which was defined as a PSA doubling time of ≤9 months. The participants were randomized 1:1:1 to either oral enzalutamide 160 mg QD plus IM leuprolide acetate 22.5 mg Q12W, leuprolide monotherapy, or enzalutamide monotherapy for 37 weeks.

If PSA was <0.2 ng/mL at week 36, treatment was suspended at week 37 and reinitiated once the PSA increased or reached the predefined thresholds as determined by PSA monitoring. Participants who did not have a PSA <0.2 ng/mL at week 36 remained on treatment.

Unprecedented survival advantage

“This unprecedented survival advantage reinforces the MFS results and further confirms enzalutamide plus ADT as the standard of care (SoC) for hrBCR prostate cancer,” Freedland concluded.

Discussant Prof Dr Derya Tilki from the Martini-Klinik Prostate Cancer Center, University Hospital Hamburg–Eppendorf in Germany, echoed Freedland’s conclusion. “EMBARK demonstrates both MFS and OS benefits for doublet therapy vs ADT alone, establishing enzalutamide plus ADT as SoC in hrBCR prostate cancer.”

Tilki added that, despite the lack of a statistically significant benefit with enzalutamide monotherapy, this remains a viable treatment alternative in this patient setting, after weighing the risks and benefits and shared decision-making.