Silke Gillessen, MD
Initial analysis from the PEACE-3 trial suggests that the addition of radium-223 dichloride to enzalutamide could offer a promising new first-line treatment option for patients with metastatic castration-resistant prostate cancer, according to data presented by lead study author, Silke Gillessen, MD, Head of Medical Oncology Department, Medical and Scientific Director, Oncology Institute of Southern Switzerland, EOC, Bellinzona, at the European Society for Medical Oncology (ESMO) Congress 2024.1
Findings from the phase III study demonstrated a statistically significant improvement in radiographic progression–free survival with the combination of radium-223 and enzalutamide, with a 31% reduction in radiologic disease progression or death compared with enzalutamide alone. This improvement was supported by statistically significant improvements in overall survival by log-rank test and time to next systemic treatment, authors of the study reported.
“These results support the combination of enzalutamide plus radium-223 plus a bone-protecting agent plus androgen-deprivation therapy as a potential new first-line treatment option for patients with [castration-resistant] prostate cancer and bone metastasis who have not received a prior androgen receptor pathway inhibitor,” said Dr. Gillessen.
As she reported, metastatic castration-resistant prostate cancer remains a challenging disease to treat, with current first-line options including androgen receptor pathway inhibitors such as enzalutamide and abiraterone. Radium-223, an alpha particle–emitting calcium mimetic, has previously shown overall survival benefits in patients with castration-resistant prostate cancer with bone metastases, said Dr. Gillessen. However, its optimal use in times of newer androgen receptor pathway inhibitors has been unclear until now.
Of note, a previous study (ERA-223) combining abiraterone with radium-223 raised concerns about increased fracture rates and no beneficial effects on survival, highlighting the importance of bone health management in these patients, said Dr. Gillessen.2
Study Design
The PEACE-3 trial is a randomized, phase III study that enrolled 426 patients across 12 countries from 2015 to 2023. Eligible patients had castration-resistant prostate cancer with bone metastases; were asymptomatic or mildly symptomatic; and had not received prior treatment with enzalutamide, apalutamide, darolutamide, or radium-223. Patients were randomly assigned 1:1 to receive either enzalutamide at 160 mg once daily (standard of care) or enzalutamide at 160 mg once daily plus radium-223 every 4 weeks for six cycles.
The primary endpoint was investigator-assessed radiographic progression–free survival, with key secondary endpoints including overall survival, safety, time to next systemic treatment, time to pain progression, and time to first symptomatic skeletal event.
Significant Reduction in Disease Progression or Death
As Dr. Gillessen reported, the combination of enzalutamide and radium-223 demonstrated a 31% reduction in the risk of radiologic disease progression or death (hazard ratio [HR] = 0.69, P = .0009). The median radiographic progression–free survival improved from 16.4 months with enzalutamide alone to 19.4 months with the combination. At 2 years, 36% of patients on enzalutamide alone were free of radiologic disease progression compared with 45% in the combination arm.
Overall survival also improved significantly in the combination arm in this interim analysis, with a 31% reduction in the risk of death compared with enzalutamide alone (HR = 0.69, P = .0031) in the log-rank test. The median overall survival increased from 35 months to 42.3 months with the combination therapy. Due to nonproportional hazards, the study will continue to a final overall survival analysis.
In addition, the time to next systemic treatment was significantly prolonged in the combination arm, with a 43% reduction in the risk of starting new systemic treatment (HR = 0.57, P < .0001). At 2 years, 51% of patients in the enzalutamide-alone group had started a new systemic treatment, compared with 30% in the combination group. No significant differences were observed in the time to pain progression or the time to symptomatic skeletal events between the two treatment arms.
Safety Profile
Regarding safety, the combination was generally well tolerated, with few patients discontinuing treatment because of toxicity, said Dr. Gillessen, who noted that grade 3 or 4 drug-related adverse events increased from 19% in the enzalutamide arm to 28% in the combination arm. The most common treatment-emergent adverse events included hypertension (approximately 30% in both arms), followed by fatigue, fracture, anemia, and neutropenia, all of which were more frequent in the combination arm. Of note, severe thrombocytopenia (grade 3 or higher) was reported in less than 2% of patients, said Dr. Gillessen. No drug-related deaths were reported.
“It’s important to note that the study protocol was amended to mandate the use of bone-protecting agents and baseline DEXA scans after observing high fracture rates in a similar trial (ERA-223),” Dr. Gillessen observed. “This resulted in over 80% of patients receiving bone-protecting agents during treatment, which likely contributed to the decreased rate of symptomatic skeletal events in both arms.”
Although these results are promising, Dr. Gillessen noted, the study’s independent data monitoring committee has recommended continuing to the final overall survival analysis to confirm the observed treatment effect due to nonproportional hazards.
Further research may explore the potential of this combination in earlier disease settings or in conjunction with other emerging therapies for prostate cancer.
EXPERT POINT OF VIEW
Karim Fizazi, MD, PhD
At the European Society for Medical Oncology (ESMO) Congress, invited discussant Karim Fizazi, MD, PhD, a medical oncologist at Institut Gustave Roussy and Professor of Oncology at the University of Paris–Saclay, underscored the clinical significance of the PEACE-3 results. He also highlighted important considerations for practical implementation and future research directions in the treatment of metastatic castration-resistant prostate cancer.
Dr. Fizazi first emphasized the significance of the PEACE consortium’s efforts in conducting academic phase III trials for prostate cancer across Europe. In just over 10 years, he noted, the consortium has completed accrual of more than 3,000 patients with prostate cancer to academic trials.
With respect to PEACE-3, Dr. Fizazi noted that although radiographic progression–free survival is a valid registrational endpoint, it does not directly measure clinical benefit to patients and is not routinely used in practice. Dr. Fizazi also highlighted the importance of the trial amendment mandating bone-protecting agents, which led to a “dramatic reduction in fracture rates postamendment,” he said. “We should use these agents in our practice more often,” he added.
Additional Commentary and Context
Regarding overall efficacy, despite some statistical caveats due to nonproportional hazards, Dr. Fizazi called the 31% reduction in the risk of death “clinically meaningful.” He anticipated that ESMO guidelines will likely be amended to reflect this combination as a potential new standard of care.
However, Dr. Fizazi cautioned that the treatment should be viewed as a “quadruplet” rather than a doublet, comprising enzalutamide, radium-223, a bone-protecting agent (denosumab or zoledronate), and androgen-deprivation therapy, with potential hypertension treatment for some patients. Dr. Fizazi also emphasized the importance of monitoring and managing hypertension in patients receiving enzalutamide.
In addition, Dr. Fizazi noted that many patients now receive androgen receptor pathway inhibitors earlier in the disease course. According to Dr. Fizazi, this shift may limit the applicability of PEACE-3 results in some clinical scenarios. He also called for more detailed data on the use of bone-protecting agents in the trial, including the specific agents used, the duration of use, and the incidence of osteonecrosis of the jaw.
Looking ahead, Dr. Fizazi mentioned the ongoing, phase III DORA and RADIANT trials, which will provide more insights into the optimal use of radium-223 in different treatment settings. “As more radium-223 phase III trials are maturing, we need to optimize its use in relation to other emerging radiopharmaceuticals, such as lutetium-177, which is also a standard of care,” Dr. Fizazi concluded.
DISCLOSURE: Dr. Gillessen reported financial relationships with Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, InnoMedica, Ipsen, MacroGenics, MSD, Novartis, AdMe Tech Foundation, Swiss group for Clinical Cancer Research (SAKK), ASCO GU, Schweizerische Gesellschaft für Medizinische Onkologie (SGMO)/Meister ConCept GmbH, ESMO, PeerVoice, Pfizer, Silvio Grasso Consulting, EPG Health, Intellisphere LLC, and Gilead Sciences; and she is the co-inventor on a patent application (WO 2009138392 A1) for a method of biomarker discovery (granted in China, Europe, Japan, and the United States). Dr. Fizazi reported financial relationships with Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, Sanofi. He serves on advisory boards for Arvinas, CureVac, MacroGenics, and Orion.
REFERENCES
1. Gillessen S, Choudhury A, Saad F, et al: A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of radium-223 and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer: First results of EORTC-GUCG 1333/PEACE-3. ESMO Congress 2024. Abstract LBA1. Presented September 13, 2024.
2. Smith M, Parker C, Saad F, et al: Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:408-419, 2019.
