Enzalutamide plus Ra223 significantly boosts rPFS in mCRPC

The combination of enzalutamide (Xtandi) plus radium-223 (Ra223, Xofigo) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases is both safe and associated with significantly improved radiological progression-free survival (rPFS), according to findings from the EORTC-GUCG 1333/PEACE-3 (NCT02194842) trial.¹

Silke Gillessen, MD

“Abiraterone [Zytiga] and enzalutamide, both androgen receptor pathway inhibitors, are the standard-of-care options for first-line treatment of patients with metastatic castration-resistant prostate cancer who progress on androgen deprivation therapy [ADT] and have not received an [androgen receptor pathway inhibitors] in [the] hormone-sensitive setting.^2,3 Of note, the current standard of care for metastatic hormone-sensitive disease is the combination of ADT plus an [androgen receptor pathway inhibitor]. However, real-life evidence shows that globally, still, many patients receive ADT only. In the setting of first-line metastatic castration-resistant prostate cancer, no combination so far has shown benefit for both radiological progression-free survival and overall survival compared to abiraterone or enzalutamide monotherapy,” said first author Silke Gillessen, MD, medical oncologist at the Oncology Institute of Southern Switzerland, Bellinzona, at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain.

Gillessen further noted that in the 2013 ALSYMPCA trial (NCT00699751), Ra223 increased OS in patients with castration-resistant prostate cancer.⁴

“However, this was in a time before the introduction of abiraterone and enzalutamide,” Gillessen said.

In addition, the ERA-223 trial (NCT02043678) evaluated the combination of abiraterone plus Ra223 vs abiraterone plus placebo. The investigators did not find a benefit symptomatic skeletal event-free survival or OS, and an increase in fractures was observed.⁵

Patients were eligible for inclusion in PEACE-3 if they had mCRPC and bone metastases, were asymptomatic or mildly symptomatic, had a WHO performance status of 0 or 1, had not received prior treatment with enzalutamide, Ra223, apalutamide (Erleada), or darolutamide (Nubeqa), no known visceral metastases, and were receiving ongoing ADT. Patients were randomly assigned 1:1 to standard-of-care enzalutamide, 160 mg once daily or enzalutamide, 160 mg once daily plus Ra223 every 4 weeks for 6 cycles. The primary end point was investigator-assessed rPFS. Key secondary end points included safety, OS, time to next systemic treatment progression, and time to first symptomatic skeletal event. Following the ERA-223 trial, the use of bone-protecting agents was made mandatory. The investigators targeted a 32% improvement in rPFS as the primary objective.

A total of 446 patients from 12 countries were enrolled from November 2015 to March 2023. Median follow-up was 42.2 months. Gillessen noted that patient characteristics were “generally well balanced,” but noted that there were more patients with increased alkaline phosphatase in the enzalutamide-alone arm.

“All 224 patients in the enzalutamide-alone arm started enzalutamide. In the combination arm, 3 patients started enzalutamide but not radium, and 4 patients didn’t start any treatment. Of note, from the patients who started the radium, almost 90% received all of the 6 planned cycles,” Gillessen noted.

Regarding rPFS, “The risk of radiological progression or death was reduced by 31% in favor of the combination of radium-223 plus enzalutamide. This was statistically significant, with a P value of .0009. In absolute terms, at 2 years, 36% of the patients in the enzalutamide-alone were free of radiological progression compared with 45% in the combination arm,” Gillessen reported.

Median OS was 35.0 months in the enzalutamide-alone arm vs 42.3 months in the combination arm.

“Due to the nonproportional hazards, the IMDC recommended to continue to the final overall survival analysis, despite this positive result, to confirm the observed treatment effect,” Gillessen said.

Regarding time to next systemic treatment, 51% of patients in the enzalutamide-alone arm started a new systemic treatment at 2 years vs 31% of patients in the combination group. There was no difference in time to pain progression or time to symptomatic skeletal event.

In terms of adverse events (AEs), “In general, the combination was very well tolerated. Only a few patients had to stop treatment due to toxicity,” Gillessen said. The investigators reported no drug-related deaths. The most common grade 3-5 treatment-emergent AEs included hypertension, fatigue, fracture, anemia, and neutropenia.

In her concluding remarks, Gillessen said, “The combination of enzalutamide and 6 cycles of radium-223 shows a statistically significant improvement in rPFS, with a 31% reduction in radiological progression or death…These results support the combination of enzalutamide plus radium-223 plus a bone-protecting agent as a potential new first-line mCRPC treatment option for patients with prostate cancer and bone metastases who have not received a prior androgen receptor pathway inhibitor.”

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 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA1. https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/session/calendar?q=LBA1

2. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148. doi:10.1056/NEJMoa1209096

3. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433. doi:10.1056/NEJMoa1405095

4. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-223. doi:10.1056/NEJMoa1213755

5. 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. 2019;20(3):408-419. doi:10.1016/S1470-2045(18)30860-X