Radium-223 Plus Enzalutamide Ups Survival in Prostate Cancer

BARCELONA, Spain — Adding bone-targeting radium-223 (Ra223) to the androgen receptor pathway inhibitor enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer and bone metastases significantly improves survival outcomes, according to the first results from the PEACE III trial.

The research, presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2024, demonstrated a 31% improvement in both progression-free survival (PFS) and overall survival in this population, none of whom had not previously received either agent. The survival benefit was also accompanied by a significant improvement in the time to the next systemic treatment.

The findings support the combination as a potential new first-line treatment option in patients with metastatic castration-resistant prostate cancer and bone metastases, said study presenter Silke Gillessen, MD, head of Medical Oncology, Università della Svizzera italiana in Lugano, and director of the Oncology Institute of Southern Switzerland in Bellinzona, Switzerland.

Karim Fizazi, MD, PhD, Gustave Roussy, Villejuif, France, who helped establish the PEACE program, but not this particular trial, agreed.

Fizazi said the results are practice changing and expects the ESMO Clinical Practice Guidelines – Prostate Cancer to be amended soon to include the combination.

But Fizazi questioned how the combination will fit into potential later lines of therapy. The current standard of care is to prescribe androgen receptor pathway inhibitors in earlier lines of therapy before the disease metastasizes or when patients are still castration sensitive. In PEACE III, the Ra223-enzalutamide combination was evaluated in patients who had not yet received one of these inhibitors, which also include abiraterone, apalutamide, and darolutamide.

Amado J. Zurita-Saavedra, MD, from MD Anderson Cancer Center, Houston, who was not involved in the trial, agreed, noting that it’s unclear whether the current findings will translate to patients who have previously received an androgen receptor pathway inhibitor.

Ra223, an alpha particle–emitting calcium mimetic that selectively targets bone metastases, has previously demonstrated a benefit in this patient population.

The ALSYMPCA trial, conducted before the introduction of enzalutamide, showed that compared with placebo, Ra223 improved overall survival in patients with metastatic castration-resistant prostate cancer with bone metastases who also received the best standard of care.

However, 2019 results from the ERA 223 trial, which combined Ra223 and the androgen receptor pathway inhibitor abiraterone, found no survival benefit with the combination in a similar patient population. In fact, the researchers revealed an increased risk for fractures and no improvement in symptomatic skeletal event-free survival with the combination vs abiraterone plus placebo.

“This really was a shock,” said Fizazi. “Nobody had expected that.”

In the current randomized controlled trial, Gillessen and colleagues made the use of bone-protecting agents mandatory partway through the trial.

Overall, 439 patients with metastatic castration-resistant prostate cancer and bone metastases received either Ra223 plus enzalutamide (n = 215) or enzalutamide alone (n = 224). Patients had asymptomatic or mildly symptomatic disease and no known visceral metastases.

Radiographic PFS was the primary endpoint.

The two treatment arms in PEACE III were well balanced in baseline characteristics. The median age was 70 years, and the median prostate-specific antigen level was approximately 24 ng/mL. About 30% patients had previously received docetaxel.

Compared with enzalutamide alone, Ra223 plus enzalutamide led to a median radiographic PFS benefit of 3 months — 19.4 vs 16.4 months (hazard ratio [HR], 0.69; P = .0009). At 24 months, 45% patients in the combination group were progression free compared with 36% in the enzalutamide group.

This small but significant PFS benefit held when stratifying patients by age, prior docetaxel use, performance status, baseline Brief Pain Inventory worst pain score, and number of focal bone lesions, as well as when evaluating patients before and after the addition of bone-protecting agents.

More notably, the combination therapy led to an overall survival benefit of 7.3 months — a median of 42.3 vs 35.0 months (HR, 0.69; P = .0031) — but the overall survival data are not yet mature.

Adding Ra223 to enzalutamide also extended the time to next systemic treatment, with 30% patients starting their next treatment at 24 months compared with almost 51% who received enzalutamide alone (HR, 0.57; P

However, the combination therapy did not lead to a benefit in time to pain progression and time to symptomatic skeletal event.

The safety analysis found that the combination therapy did result in more grade 3-5 drug-related adverse events, which occurred in 28% patients vs 19% with enzalutamide alone. There were no deaths due to drug-related adverse events in either group, but seven deaths (3%) related to an adverse event in the combination group and four (2%) in the enzalutamide group.

Fatigue, fracture, anemia, and neutropenia were all more common with the addition of Ra223. The most common adverse event in both the groups was hypertension, seen in approximately 34% patients.

Enzalutamide is “clearly associated with an excess in hypertension,” said Fizazi, which means “we need monitor blood pressure, and we need to treat these patients when they develop hypertension.”

Fizazi also highlighted that although the use of bone-protecting agents protected against fractures, the incidence of osteonecrosis of the jaw, a rare adverse event associated with the drugs, has not yet been reported for PEACE III.

This adverse event “will be key to look at,” he emphasized, because “we don’t want the patients to pay the price in terms of their jaw.”

Consequently, the mandatory use of bone-protecting agents means the doublet of Ra223 plus enzalutamide will likely become a quadruplet treatment, particularly as antihypertension treatment may be necessary.

Another wrinkle, Zurita-Saavedra noted, is the availability of a newer radioligand therapy, Lutetium-177 PSMA, which has broader activity than Ra223. Despite many years of using Ra223, “there is not a clear sense of who’s the best candidate” for Ra223 vs Lutetium-177 PSMA.

Michael Hofman, MD, of Peter MacCallum Cancer Centre in Melbourne, Australia, agreed that the treatment landscape may have already shifted to this newer radioligand therapy; he did wonder whether the PEACE III trial may have reinvigorated the role of Ra223. The PEACE III trial results were “much more impressive than I expected,” he wrote on X, suggesting a possible role for combining the two agents.

The study was funded by Bayer HealthCare Pharmaceuticals and Astellas Pharma Europe. Gillessen declared relationships with Bayer and Astellas, as well as other companies, including Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, and Pfizer. Fizazi declared relationships with Astellas and Bayer, as well as AstraZeneca, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, Sanofi, Arvinas, CureVac, MacroGenics, and Orion. Zurita-Saavedra declared relationships with Bayer and Astellas, as well as Merck, Pfizer, and others.