Addition of Radium-223 to Enzalutamide Significantly Improves rPFS and OS in mCRPC

The addition of Radium-223 (Xofigo) to enzalutamide (Xtandi) yielded significant improvements in radiological progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) and predominant bone metastases, according to data from the phase 3 PEACE-3 trial (NCT02194842). Findings presented at the 2024 ESMO Congress also noted that if the combination is used, a bone-protecting agent will be mandatory.¹

“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,” Silke Gillessen, MD, a medical oncologist at Università della Svizzera italiana in Lugano, Switzerland, said in a presentation of findings.

There was a statistically significant improvement seen regarding the primary end point of rPFS in patients who received Radium-223 plus enzalutamide (n = 222) vs enzalutamide alone (n = 224). The median rPFS was 19.4 months (95% CI, 17.1-25.3) in the doublet arm compared with 16.4 months (95% CI, 13.8-19.2) in the monotherapy arm (HR, 0.69; 95% CI, 0.54-0.87; log-rank P = .0009). The 24-month rPFS rates were 45% vs 36%, respectively. Gillessen noted that the treatment effect on rPFS with the doublet vs monotherapy was consistent across all subgroups analyzed.

Further, at the interim analysis with 80% of OS events having occurred, the median OS was 42.3 months (95% CI, 36.8-49.1) in the Radium-223 plus enzalutamide arm vs 35.0 months (95% CI, 28.8-38.9) in the enzalutamide arm (HR, 0.69; 95% CI, 0.52-0.90; log-rank P = .0031).

“The HR for OS was also 0.69 with a statistically significantly positive P value,” Gillessen said. “Due to the non-proportional hazards [it was] recommended to continue to the final OS analysis despite this positive result, to confirm the observed treatment effect. Time to next systemic treatment [TTNT] was also statistically significantly prolonged in the combination arm [vs monotherapy arm].”

Enrollment Criteria for the Global PEACE-3 Study

Patients from 12 countries with mCRPC and bone metastases who were receiving androgen deprivation therapy were enrolled in PEACE-3. Additionally, patients must have had a WHO performance score of 0 or 1 and asymptomatic or mildly symptomatic disease. Prior treatment with Radium-223 or enzalutamide was not permitted and patients were not eligible for enrollment if they had known visceral metastases.

Following 1:1 random assignment, patients were stratified by country, baseline pain (Brief Pain Inventory [BPI] worst pain score of 0-1 vs 2-3), prior use of docetaxel (yes vs no), prior use of abiraterone (Zytiga; yes vs no), and use of bone protecting agents (yes vs no). However, after 119 patients were enrolled, investigators made the use of bone protecting agents mandatory.

Patients received enzalutamide once daily at 160 mg in both arms, and those in the combination arm also received Radium-223 at 55 kBq/kg intravenously every 4 weeks for 6 cycles. The primary end point of the study was rPFS and key secondary end points included safety, OS, TTNT, time to pain progression, and time to first symptomatic skeletal event (SSE).

The median age of patients enrolled was 70.0 years (43.0-90.0) in the combination arm and 70.0 years (47.0-90.0) in the monotherapy arm. Patients had median prostate-specific antigen levels of 25.3 ng/mL (range, 6.5-68.8) vs 23.0 ng/mL (range, 8.5-54.9), respectively.

Additionally, baseline patient characteristics were generally well balanced; in the combination arm vs monotherapy arm, patients had extra-skeletal disease at baseline (35% vs 33%), a WHO performance status of 0 (69% vs 69%), received prior docetaxel (30.2% vs 30.0%), and received prior abiraterone (2.0% vs 3.0%), respectively. Patients had at least 10 bone lesions (42% vs 44%), less than 10 bone lesions (49% vs 47%), or had missing/diffuse lesions (9% vs 9%) and had alkaline phosphatase levels above the upper limit of normal (37% vs 49%) and at/below the upper limit of normal (57% vs 48%), respectively.

TTNT Improved, But Time to Pain Progression and SSE Did Not With Doublet vs Monotherapy

Patients experienced a significant improvement in TTNT when they received Radium-223 plus enzalutamide vs enzalutamide alone (HR, 0.57; 95% CI, 0.44-0.75; P < .0001). At 24-months, the estimated proportion of patients who started the next systemic treatment was 29.9% (95% CI, 23.6%-36.4%) in the doublet arm vs 50.9% (95% CI, 43.6%-57.6%) in the monotherapy arm.

“There was no difference in time to pain progression,” Gillessen noted. “There was also no difference in the time to SSE. Of note, because we made the bone protecting agent mandatory, we had more than 80% of patients in both arms who had [received] a bone protecting agent during their treatment. Before the amendment, only approximately half of the patients received a bone protecting agent.”

The estimated proportion of patients with pain progression at 24-months in the modified population—excluding those with opioid use and with a BPI WP24 pain score of 9 or greater at study entry—was 48.3% (95% CI, 40.8%-55.3%) in the doublet arm (n = 206) vs 44.6% (95% CI, 37.3% vs 51.6%) in the monotherapy arm (n = 203; HR, 1.02; 95% CI, 0.77-1.36; fine and gray P = .5341).

Additionally, the estimated proportion of patients with a SSE at 24-months was 17.8% (95% CI, 12.9%-23.4%) in the doublet arm vs 18.0% (95% CI, 13.2%-23.4%) in the monotherapy arm. The HR was 0.93 but investigators noted there was no formal comparison as the previous end point was not significant. Further, 81.5% vs 84.4% of patients, respectively, received a bone protecting agent.

Safety Findings in PEACE-3

Data from the safety population of the Radium-223 plus enzalutamide arm (n = 218) vs enzalutamide monotherapy arm (n = 224) revealed that 84% of patients vs 71% of patients experienced drug-related adverse effects (AEs), respectively. Patients in the combination arm vs monotherapy arm experienced serious AEs (43% vs 30%), serious drug-related AEs (8% vs 1%), grade 3 to 5 AEs (66% vs 56%), and grade 3 to 5 drug-related AEs (28% vs 19%), respectively.

Seven patients in the combination arm died due to an AE compared with 4 patients in the monotherapy arm; notably, no deaths were a result of drug-related AEs.

Additionally, treatment discontinuation rates due to toxicity were 11% in the doublet arm compared with 7% in the monotherapy arm. The most common grade 3 to 5 treatment-emergent AEs that occurred were hypertension (33.5% vs 34.4%), fatigue (5.5% vs 1.8%), fracture (5.1% vs 1.3%), anemia (4.6% vs 2.2%), neutropenia (4.6% vs 0), bone pain (4.1% vs 4.9%), decreased weight (3.2% vs 0.4%), and spinal cord compression (2.8% vs 3.6%). Treatment-related AEs included hypertension (11.5% vs 12.1%), fatigue (4.1% vs 1.3%), anemia (2.8% vs 0.0%), and neutropenia (3.2% vs 0.0%), respectively.

“In general, before using this combination fully in our patients, I believe we need more data,” Karim Fizazi, MD, PhD, a medical oncologist at Institute Gustave Roussy in Villejuif, France, said in discussion of the study findings. Fizazi noted that data from more phase 3 trials evaluating Radium-223 are currently maturing.

Disclosures: Gillessen cited receiving personal honoraria as an invited speaker for Swiss group for Clinical Cancer Research, ESMO, Schweizerische Gesellschaft für Medizinische Onkologie (SGMO)/Meister ConCept GmbH. She has received institutional honorarium for participation in advisory boards or independent Data Monitoring Committees and Steering Committees from Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Innomedica, Ipsen, Macrogenics, MSD, and Novartis, and was an invited speaker for AdMe Tech Foundation, Swiss group for Clinical Cancer Research, ASCO GU, (SGMO)/Meister ConCept GmbH, ESMO, PeerVoice, Pfizer, Silvio Grasso Consulting, EPG Health, and Intellisphere LLC. She has also received travel grants from Bayer, Gilead, and Intellisphere. Gillessen is a coinventor on patent application for a method for biomarker discovery granted in China, Europe Japan, and the US (WO 2009138392 A1).

Reference

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 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA1.