Enzalutamide and Radium-233 Extend Survival in Metastatic Castration-Resistant Prostate Cancer

Adding enzalutamide (Xtandi; Astellas Pharma US, Inc) to 6 cycles of radium Ra 223 dichloride (Xofigo; Bayer HealthCare Pharmaceuticals Inc) led to meaningful improvements in survival for patients with metastatic, castration-resistant prostate cancer (mCRPC) in the randomized, phase 3 PEACE-3 trial (NCT02194842). The data were presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.^1,2

Enzalutamide and CRPC

Prostate cancer is the most common cancer and the second leading cause of cancer-related deaths in men in the United States, affecting an estimated 333,830 individuals in 2026 alone. According to the American Cancer Society, about 1 in 8 men will be diagnosed with prostate cancer in their lifetime.³

Although treatment options have yielded 5-year survival rates of over 90% for patients with localized prostate cancer, approximately 10% to 20% of patients will develop mCRPC within 5 years of their initial diagnosis. mCRPC represents an aggressive, advanced type of prostate cancer that is resistant to hormone therapies—the typical front-line treatment many patients receive—leaving many without adequate treatment options.^4,5

Enzalutamide is an oral androgen receptor inhibitor that induces the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19. These enzymes are strong inducers of CYP3A4, a gene responsible for prostate cancer and a driver of aggressive disease.^6,7

According to PEACE-3 trial data, enzalutamide demonstrated significant clinical efficacy when used in combination with radium-233, a radioactive isotope that kills cells by emitting low levels of alpha particle radiation (100 µm), causing double-strand DNA breaks. It is particularly effective at treating bone metastases due to its “calcium mimetic” properties, which allow it to accumulate in areas of bone undergoing increased cell turnover.⁸

PEACE-3 Methods and Design

PEACE-3 is a randomized, multicenter phase 3 trial comparing enzalutamide with or without radium-233 in asymptomatic or mildly symptomatic CRPC with approximately 2 bone metastases. A total of 466 patients were randomly assigned 1 :1 to receive either enzalutamide at 160 mg daily alone, or in combination with 6 intravenous injections of radium-223 (55 kBq/kg every 4 weeks).⁹

The primary end point was radiological progression-free survival (rPFS) with secondary end points of overall survival (OS) and safety.⁹

Enzalutamide Survival Benefits

In the previously published primary analysis, treatment with enzalutamide plus radium-223 was associated with a statistically significant improvement in rPFS. Median rPFS was 19.4 months with the combination compared with 16.4 months with enzalutamide alone, corresponding to an HR of 0.69 (95% CI, 0.54-0.87; P = .0009).⁹

The final OS analysis data further substantiated these findings. Median OS was 38.2 months with the combination vs 32.6 months with enzalutamide monotherapy, yielding an HR of 0.75 (95% CI, 0.60-0.95). This met the prespecified criterion for statistical significance, with a one-sided stratified log-rank P-value of .0078 (final analysis significance threshold, < 0.0248). Results from a supportive permutation test confirmed the robustness of the OS benefit, producing a one-sided P-value of .0088.⁹

The OS advantage was generally consistent across predefined subgroups, with the exception of patients older than 75 years, in whom a statistically significant interaction was observed at the 10% two-sided level.⁹

Safety and Toxicity Profile of Enzalutamide Plus Radium-233

The combination led to a moderate but manageable increase in toxicity. Overall, grade 3 to 5 drug-related adverse events (AEs) occurred in 29% of patients in the combination arm and 19% in the control arm, with no drug-related deaths. Treatment discontinuation due to toxicity was also low in both arms.⁹

"Looking at specific grade 3 to 5 [AEs], hypertension was the most common in both arms,” explained Enrique Gallardo, MD, from the Parc Taulí University Hospital, Parc Taulí Institute of Research and Innovation I3PT, Autonomous University of Barcelona in Spain. “For the combination arm, there was an increase in fatigue, fractures, anemia, and neutropenia. Importantly, no individual [AE] increased more than 5%. Grade 3 to 5 [AEs] increased more than 5% in the combination arm."²

Gallardo highlights a few key safety findings pharmacists should be aware of. In the combination arm, 3 patients developed hematologic malignancies. The researchers also reported 17 cases of osteonecrosis of the jaw, 14 of which were in the combination arm. Five cases were grade 3.⁹

“The safety profile observed a moderate but manageable increase in toxicity for the combination arm,” he said.²

Conclusion

Taken together, the PEACE-3 findings reinforce the clinical value of combining enzalutamide with radium-233 in appropriately selected patients with mCRPC and bone metastases. The demonstrated improvements in both rPFS and OS, coupled with a manageable and well-characterized safety profile, suggest this regimen may represent a meaningful first-line treatment option when used alongside bone-protecting agents.

As treatment paradigms for advanced prostate cancer continue to evolve, these data from the PEACE-3 trial provide important guidance for clinicians and pharmacists seeking to optimize outcomes while balancing efficacy and toxicity in this high-risk population.

REFERENCES

1. Phase III radium 223 mCRPC-PEACE III (PEACE III). Clinicaltrials.gov. Updated September 19, 2025. Accessed February 26, 2026. https://clinicaltrials.gov/study/NCT02194842

2. Bossi A, Barragan-Carillo R, Apolo A, et al. Oral abstract session A: prostate cancer. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 26-28, 2026; San Francisco, CA.

3. Prostate cancer—patient version. National Cancer Institute. Accessed February 26, 2026. https://www.cancer.gov/types/prostate

4. Survival rates for prostate cancer. American Cancer Society. Updated January 13, 2026. Accessed February 26, 2026. https://www.cancer.org/cancer/types/prostate-cancer/detection-diagnosis-staging/survival-rates.html

5. Candelieri-Surette D, Lee JS, Lynch J, et al. Epidemiology of metastatic castration-resistant prostate cancer in veterans nationwide. J Natl Compr Canc Netw. 2025;23(8):307-313. doi:10.6004/jnccn.2025.7032

6. Lennep BW, Mack J, Poondru S, et al. Enzalutamide: understanding and managing drug interactions to improve patient safety and drug efficacy. Drug Saf. 2024;47(7):617-641. doi:10.1007/s40264-024-01415-7

7. Bellah SF, Salam MA, Billah SMS, Karim MR. Genetic association in CYP3A4 and CYP3A5 genes elevate the risk of prostate cancer. Ann Hum Biol. 2023;50(1):63-74. doi:10.1080/03014460.2023.2171122

8. Radium-223 improves survival in patients with advanced prostate cancer. National Cancer Institute. August 2, 2013. Accessed February 26, 2026. https://www.cancer.gov/types/prostate/research/radium-223-improves-survival

9. Gallardo E, Tombal B, Choudhury A, et al. Final overall survival results from the EORTC 1333/PEACE-3 trial: enzalutamide with or without radium-233 in metastatic castration-resistant prostate cancer. Abstract presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 26-28, 2026; San Francisco, CA. Abstract 15.