Adding Xofigo to Xtandi extends survival and delays disease progression in men with metastatic castration-resistant prostate cancer with bone involvement.
The combination of Xtandi (enzalutamide) with Xofigo (radium-223) demonstrated a clinically meaningful improvement in overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, according to final data from the phase 3 EORTC 1333/PEACE-3 trial presented by Dr. Enrique Gallardo at the
Moreover, findings also confirmed a durable improvement in radiographic progression-free survival (rPFS) with manageable toxicity in the combination arm, supporting Xtandi plus radium-223 as a valid first-line treatment option for patients with bone-predominant mCRPC.
“The combination of Xtandi and six cycles of radium-223 demonstrated a significant overall survival benefit, confirming the previously reported improvement in radiographic progression-free survival, with a moderate increase in adverse events [AEs],” Gallardo, of the Parc Taulí Hospital Universitar, said during his presentation.
The combination of Xtandi plus radium-223 significantly improved OS compared with enzalutamide alone. The median OS was 38.21 months (with the combination versus 32.62 months for enzalutamide alone.
Xtandi and Xofigo independently have shown OS benefit in mCRPC, leading to the hypothesis that combining these agents could provide complementary mechanisms of action and enhanced outcomes. Earlier analyses from the PEACE-3 trial, reported at previous ESMO Congresses and published in Annals of Oncology, demonstrated that Xtandi plus Xofigo significantly improved rPFS compared with Xtandi alone. Notably, the combination led to a moderate increase in toxicity. The current presentation updates these findings with final OS data as a key prespecified secondary endpoint.
PEACE-3 was a multicenter, randomized, open-label phase 3 trial conducted across 56 centers in 12 countries. It enrolled patients with asymptomatic or mildly symptomatic mCRPC with bone metastases and no visceral disease. Patients were randomly assigned 1:1 to receive 160 mg of Xtandi once daily plus 55 Bq/kg of intravenous Xofigo every 4 weeks for six cycles (222 patients) or 160 mg of Xtandi once daily alone (224 patients). Stratification factors included country, baseline pain, prior chemotherapy with docetaxel, use of bone-targeting agents, and prior abiraterone therapy. After March 2018, bone-protecting agents were mandated due to fracture risk data.
Metastatic castration-resistant prostate cancer (mCRPC): Advanced prostate cancer that continues to grow despite hormone-lowering therapy.
Overall survival (OS): How long patients live after starting treatment.
Radiographic progression-free survival (rPFS): The time during which cancer does not worsen on imaging scans.
From November 2015 to March 2023, 446 patients were enrolled. Median age was 70 years across both treatment arms. In the combination arm, 30% of patients had received prior docetaxel compared with 30% in the Xtandi-alone arm. Two percent of patients in the combination arm received prior abiraterone (Zytiga) versus 3% with Xtandi alone. In the combination arm, 42% of patients had 10 or more bone lesions compared with 44% in the single-agent arm; for patients with fewer than 10 bone lesions, these numbers were 49% and 47%, respectively. Additionally, 35% versus 33% of patients in each group had extra-skeletal disease at baseline. The median follow-up for the final OS analysis was 4.8 years.
At the time of final analysis, 317 deaths had occurred: 152 in the combination arm and 165 in the single-agent arm. Disease progression was the primary cause of death in both arms (72% in each group). Other causes included cardiovascular disease (4.6% versus 4.8%), non-malignant disease (0% versus 1.8%), new malignancy not related to prostate cancer (1.3% versus 1.2%), other causes (9.2% versus 9.5%), and unknown causes (11.8% versus 13.3%). No drug-related deaths were reported.
Survival rates for the combination and single-agent therapy at key time points were as follows: six-month survival was 97% and 99%, 12-month survival was 91% and 93%, 18-month survival was 81% and 81%, 24-month survival was 71% and 68%, and 36-month survival was 54% and 47%, respectively.
Gallardo noted, “The survival curves crossed around month 18, with a small number of early deaths in the combination arm, but after 18 months, the benefit clearly favored the combination.”
Subgroup analyses showed consistent OS benefit across most populations, though it was less pronounced in older patients, those with prior docetaxel exposure, or those with poorer performance status. The previously reported rPFS improvement was confirmed with longer follow-up, with median rPFS of 19.2 months in the combination arm versus 16.4 months for Xtandi alone, demonstrating the durability of benefit for the combination.
Treatment with Xtandi plus Xofigo was associated with a moderate increase in side effects. Treatment-emergent adverse events occurred in nearly all patients in both groups, with drug-related adverse events reported in most patients. Serious adverse events occurred in approximately half of patients in the combination group compared with one-third in the single-agent group. Grade 3 to 5 adverse events occurred in 69% of patients in the combination arm and 58% in the single-agent arm. Deaths due to drug-related adverse events were rare, 4.6% in the combination arm versus 2.7% in the single-agent arm. Discontinuation due to toxicity was low in both groups.
“Hypertension was the most common severe adverse event in both arms,” Gallardo reported. “We observed modest increases in fatigue, fractures, anemia, and low white blood cell counts, but no individual severe adverse event increased by more than 5% in the combination arm.” Three cases of blood cancers were reported in the combination arm, along with 14 cases of osteonecrosis compared with 5 in the control arm, five of which were severe. Overall, the safety findings support the combination as manageable for appropriately selected patients.
While the combination provides meaningful survival benefit, the trial population primarily included patients previously treated with androgen deprivation therapy alone or in combination with chemotherapy, which represents a limitation.
Gallardo concluded, “With a median follow-up of nearly five years, Xtandi plus six cycles of Xofigo demonstrated clinically meaningful OS benefit with a median gain of 5.6 months. The improvement in rPFS is confirmed, and the safety profile shows a moderate but manageable increase in toxicity. Based on these results, this combination represents a first-line option for patients with mCRPC with bone metastases, in conjunction with a bone-protecting agent as standard of care.”
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