Enzalutamide Intensifies the Activity of ADT Monotherapy and Expands Limited nmCSPC Treatment Armamentarium

The FDA approval of enzalutamide (Xtandi) in nonmetastatic castration-sensitive prostate cancer (nmCSPC) addresses the longstanding need for effective alternatives to hormonal therapy that can delay disease progression for patients with high-risk biochemical recurrence and demonstrates the viability of using more targeted approaches in this disease state, according to Neal Shore, MD, FACS.

The agent was evaluated in the phase 3 EMBARK trial (NCT02319837), in which the addition of enzalutamide to leuprolide (n = 355) significantly improved metastasis-free survival (MFS) vs leuprolide (Lupron) alone (n = 358), with a median that was not yet reached in either arm (HR, 0.42; 95% CI, 0.30-0.61; P < .0001).¹ The 3-year MFS rates were 92.9% with the enzalutamide combination and 83.5% with the placebo regimen; corresponding 5-year MFS rates were 87.3% and 71.4%, respectively.

Based on these data, the FDA approved enzalutamide for patients with nmCSPC and biochemical recurrence at high risk for metastasis on November 17, 2023.²

“This is the first longitudinal, prospective, randomized trial demonstrating the highest level of evidence that combination enzalutamide plus an LHRH [luteinizing hormone–releasing hormone] agonist is superior to LHRH monotherapy in terms of delaying metastasis and improving MFS,” said Shore, who is the US chief medical officer of surgery and oncology at GenesisCare USA, and the medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina. “We’re still following these patients for overall survival [OS], but [that is] also trending in favor of the combination.”

In an interview with OncLive®, Shore highlighted the efficacy achieved with enzalutamide plus leuprolide in the EMBARK study, discussed toxicities observed with enzalutamide alone or in combination with a LHRH agonist, and emphasized the significance of the FDA approval of enzalutamide in this population.

OncLive: Please expand on the design and methodology of the EMBARK trial in nmCSPC.

Shore: EMBARK was a global, prospective, 3-arm trial enrolling a little over 1,000 patients. These patients had previously undergone prostatectomy [with or without] radiation therapy for localized disease. We looked at prostate-specific antigen doubling times [in patients who had developed biochemical recurrence]. These had to be 9 months or less. In one arm, patients received standard LHRH therapy with placebo. Another arm received the LHRH alongside 160 mg of enzalutamide, which is its approved dose throughout the continuum of approvals it has received. [Patients in] the third arm [received] open-label enzalutamide monotherapy at 160 mg daily. All the patients who received the LHRH were blinded, as opposed to [those in] the monotherapy arm. The key primary end point was MFS, which is a composite of radiographic progression and/or death of any cause.

What key efficacy findings from EMBARK supported this regulatory decision?

After over 8 years of collecting [data from] these patients, [including assessment of] a significant number of patients at the 3- and 5-year marks, we saw that the combination arm [was superior to] the LHRH placebo arm [in terms of MFS] with a hazard ratio of approximately 0.42. In other words, [the combination produced] a 58% improvement in MFS. OS has not yet achieved statistical significance, but it’s clearly trending [in favor of the enzalutamide regimen], with confidence intervals that are already less than 1. The monotherapy enzalutamide arm bested the LHRH arm with a HR for metastasis or death of 0.63, or a 37% improvement in MFS.

What should be known about the safety profile of the regimen in this disease?

We saw no new safety signals for enzalutamide in the combination arm compared with the monotherapy LHRH arm [in EMBARK]. We’ve had over a decade of [experience] using enzalutamide in mCRPC before or after chemotherapy, [based on data from] the [phase 3] AFFIRM [NCT00974311] and PREVAIL [NCT01212991] trials, respectively. [We also have data on enzalutamide from] the nonmetastatic castration-resistant prostate cancer arm from the phase 3 PROSPER trial [NCT02003924]. With the [phase 3] ARCHES [NCT02677896] and ENZAMET [NCT02446405] trials in metastatic hormone-sensitive prostate cancer, we know that there are some issues with adding an androgen receptor pathway inhibitor [ARPI] to androgen deprivation therapy [ADT] testosterone suppression, but [there were] no new safety signals.

In the monotherapy enzalutamide arm where there’s no testosterone suppression, we do see some more breast-related adverse effects, [including] nipple tenderness, gynecomastia, and even nipple pain. We’ve seen this in other enzalutamide monotherapy studies, such as the large, phase 2 ENACT trial [NCT02799745] that I had the privilege of leading. Interestingly, we didn’t use any prophylactic strategies in EMBARK to try and obviate or prevent [these toxicities.] There are strategies that one can use, including prophylactic radiation, which can be done over [the course of] 1 to 2 days on an outpatient basis. Some people have had experience using aromatase inhibitors, and there is even potential outpatient subareolar incisions that can be made to remove the breast tissue. That area is ripe for additional study and education.

What is the significance of the FDA approval of enzalutamide for this patient population, and how does enzalutamide fit into the treatment paradigm in nmCSPC?

For years, we’ve been treating patients with testosterone suppression in the form of ADT for these patients who have [progressed on or after] surgery, prostatectomy, radiation, and external beam radiation therapy with or without radiation therapy, or combinations of those. We had no level 1 evidence [for] just using monotherapy ADT, but that was the paradigm. Now, we see along with so many other treatments in the prostate cancer [armamentarium], that intensifying ADT monotherapy by adding an ARPI such as enzalutamide [is a viable strategy]. Here, in [patients with a high risk of biochemical recurrence.] that combination of ADT and enzalutamide is superior in terms of disease progression compared with monotherapy LHRH. Even ARPI monotherapy is superior to LHRH monotherapy. We see this when we look at the clinical benefit of delaying disease progression.

We have some additional data on patient-reported outcomes [PROs] that were presented and published simultaneously in the New England Journal of Medicine. [These] findings [showed that] patients [treated] with [enzalutamide] monotherapy experienced an improvement in their sexual function. Looking at various FACT-P subscales and EORTC-QLQ–validated questionnaires, we also demonstrated that there was overall comparability in PROs. That’s reassuring when you’re combining therapy as opposed to just giving LHRH monotherapy.

Now that the FDA has approved the label expansion [for enzalutamide in high-risk biochemically recurrent disease], the discussion should be [about the potential benefit of] combining LHRH with enzalutamide vs enzalutamide monotherapy. We are following these patients for OS, and we’ll probably [release] a report on that sometime in 2025.

References

1. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. doi:10.1056/NEJMoa2303974
2. Pfizer and Astellas' Xtandi approved by U.S. FDA in earlier prostate cancer treatment setting. News release. Astellas. November 17, 2023. Accessed January 9, 2024. https://www.astellas.com/en/news/28626