Alicia Morgans, MD, MPH, discusses data from the PEACE-3 trial that support the use of radium-223 plus enzalutamide in patients with mCRPC.
The combination of radium-223 (Xofigo) and enzalutamide (Xtandi) has shown survival benefits compared with enzalutamide monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), although questions remain regarding its efficacy in patients with prior androgen receptor pathway inhibitor (ARPI) exposure, according to Alicia Morgans, MD, MPH.
“It’s important, as we live and practice in a contemporary time where many patients get these prior exposures, to try to get to the bottom of [the question of the role of radium-223 in mCRPC management],” Morgans said in an interview with OncLive®.
In the interview, Morgans discussed data from the phase 3 PEACE-3 trial (NCT02194842) that support the use of radium-223 plus enzalutamide in patients with mCRPC, remaining questions regarding the efficacy of the PEACE-3 regimen in patients who have previously received agents like apalutamide (Erleada) and darolutamide (Nubeqa), and how the ongoing phase 3 DORA trial (NCT03574571) may further clarify the use of radium-223 in prostate cancer management.
Morgans is a genitourinary medical oncologist and director of the Survivorship Program at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.
PEACE-3 Trial: Key Takeaways
Combining enzalutamide with radium-223 in patients with mCRPC significantly improved the primary end point of radiological progression-free survival, which increased from 16.4 months (95% CI, 13.8-19.2) in the enzalutamide arm to 19.4 months (95% CI, 17.1-25.3) in the combination arm (HR, 0.69; 95% CI, 0.54-0.87; P = .0009).
An interim analysis of overall survival (OS) suggested a significant advantage with the combination therapy, with a median OS of 42.3 months (95% CI, 36.8-49.1) vs 35.0 months (95% CI, 28.8-38.9) with enzalutamide alone (HR 0.69; 95% CI, 0.52-0.90; P = .0031), although the study will continue to the final OS analysis due to non-proportional hazards.
The incidence of fractures was higher in the combination arm (24.3%) compared with in the enzalutamide arm (13.4%), underscoring the importance of mandating the co-administration of bone-protecting agents after a protocol amendment prompted by safety concerns from a companion trial.
OncLive: What did the PEACE-3 trial demonstrate regarding the clinical benefit of radium-223 with or without enzalutamide vs enzalutamide monotherapy in patients with mCRPC?
Morgans: PEACE-3 was an important study in first-line mCRPC that included patients who had been treated with androgen deprivation therapy [ADT] and potentially docetaxel in the metastatic hormone-sensitive setting. [In this trial, patients received] enzalutamide with or without radium-223 in that first-line, mCRPC setting.1 [This trial] was important because we have both enzalutamide and radium-223 available to us in routine clinical care. Enzalutamide has been a strong standard-of-care treatment in this setting for a long time, [so there] remains a high bar to go above if you’re going to have a clinical trial with that as the comparator. What was important about PEACE-3 is that we saw that both radiographic progression-free survival and overall survival were improved with the addition of radium-223 to enzalutamide when compared with that strong enzalutamide control arm. [This shows that] for patients who have metastatic disease that’s bone predominant, even with some lymph node involvement, [radium-223 plus enzalutamide] is a new standard, if they’ve only received ADT or ADT plus docetaxel in an earlier state.
What questions remain about the applicability of the PEACE-3 results, particularly for patients who have received prior enhanced hormonal therapy?
If a patient has already received an ARPI, does [enzalutamide] add to a backbone, or should [the patient receive] radium-223 alone if radium-223 is the right option for them to receive? That answer is still outstanding. For patients who have had abiraterone exposure, it’s reasonable to consider switching to enzalutamide plus radium-223 as a doublet therapy for patients with first-line mCRPC, if they meet the criteria in terms of being asymptomatic, having bone-predominant metastatic disease, and having lymph node involvement, as long as they don't have visceral involvement, which was an exclusion criterion in the trial. That’s reasonable, particularly if a patient wants to be more aggressive in their treatment, because the potential upside is high here.
However, the data do not exist to tell us exactly what the additive benefit of enzalutamide to radium-223 is vs radium-223 alone in a patient population that has already received abiraterone. When it comes to other ARPIs, the expected cross-resistance related to prior exposure to apalutamide or darolutamide, for example, when given before enzalutamide, is that enzalutamide probably has little to no effect in that post-AR inhibitor setting. I don’t know that I would choose the doublet of radium-223 and enzalutamide in that setting. However, this is an area that needs ongoing investigation.
What ongoing research may further clarify the optimal role of radium-223 in mCRPC management?
There are multiple ongoing studies that include radium-223. One is the DORA trial, which includes patients who receive a combination of radium-223 and docetaxel.2 That has been going on for a long time. There is a lot of enthusiasm around whether there might be synergistic activity there for this combination, and it might be another trial that surprises us and upends our understanding of giving a standard treatment, potentially with radium-223, to have additive—at minimum—or perhaps even synergistic benefits.
That is a trial you should keep your eye on. It is being run through the Prostate Cancer Clinical Trials Consortium group that has many dedicated sites and lots of patients involved. We are hopeful to see [the results from] this in the relatively near future.
References
Tombal B, Choudhury A, Saad F, et al. Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: results of the EORTC 1333/PEACE-3 trial. Ann Oncol. 2025;36(9):1058-1067. doi:10.1016/j.annonc.2025.05.011
2.A study to test radium-223 with docetaxel in patients with prostate cancer. ClinicalTrials.gov. Updated August 17, 2025. Accessed October 14, 2025. https://www.clinicaltrials.gov/study/NCT03574571
