CORRECTING and REPLACING New XOFIGO® (radium-223 dichloride) Data in Metastatic Castration-Resistant Prostate Cancer from Phase III PEACE III Trial Published in Annals of Oncology

• XOFIGO^® (radium-223 dichloride) in combination with enzalutamide significantly increased radiological progression-free survival (rPFS) for patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, with a 31% reduction in the risk of progression or death compared to enzalutamide alone (HR 0.69; 95% CI, 0.54-0.87; p=0.0009)
• At the pre-planned interim analysis, patients treated with XOFIGO in combination with enzalutamide also demonstrated statistically significant overall survival (OS), with a 31% reduction in the risk of death (HR 0.69; 95% CI 0.52-0.90; p=0.0031), and a median OS of 42.3 months (95% CI 36.8-49.1) for XOFIGO plus enzalutamide compared to 35.0 months (95% CI 28.8-38.9) in the enzalutamide arm
• Results were previously presented as a late-breaking abstract during the Presidential Symposium at the European Society of Medical Oncology (ESMO) 2024 Annual Meeting

Reissuing release to remove eighth paragraph.

The updated release reads:

NEW XOFIGO^® (RADIUM-223 DICHLORIDE) DATA IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER FROM PHASE III PEACE III TRIAL PUBLISHED IN ANNALS OF ONCOLOGY

• XOFIGO^® (radium-223 dichloride) in combination with enzalutamide significantly increased radiological progression-free survival (rPFS) for patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, with a 31% reduction in the risk of progression or death compared to enzalutamide alone (HR 0.69; 95% CI, 0.54-0.87; p=0.0009)
• At the pre-planned interim analysis, patients treated with XOFIGO in combination with enzalutamide also demonstrated statistically significant overall survival (OS), with a 31% reduction in the risk of death (HR 0.69; 95% CI 0.52-0.90; p=0.0031), and a median OS of 42.3 months (95% CI 36.8-49.1) for XOFIGO plus enzalutamide compared to 35.0 months (95% CI 28.8-38.9) in the enzalutamide arm
• Results were previously presented as a late-breaking abstract during the Presidential Symposium at the European Society of Medical Oncology (ESMO) 2024 Annual Meeting

Annals of Oncology published full results from the pivotal investigational Phase III PEACE III trial, evaluating XOFIGO^® (radium-223 dichloride) in combination with enzalutamide, an AR pathway inhibitor (ARPI), versus enzalutamide alone in the first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases.¹

XOFIGO is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.²

Initially presented as a late-breaking abstract during the Presidential Symposium at ESMO 2024, results demonstrated that the addition of XOFIGO to enzalutamide significantly increased radiological progression-free survival (rPFS) for patients with mCRPC with bone metastases, with a 31% reduction in the risk of progression or death (HR 0.69; 95% CI, 0.54-0.87; p=0.0009) compared to enzalutamide alone.^1,3 Patients receiving XOFIGO in combination with enzalutamide had a median rPFS of 19.4 months (95% CI, 17.1-25.3 months) compared to 16.4 months (95% CI, 13.8-19.2 months) with enzalutamide, a 3-month difference in median rPFS.^1,3 The trial was a collaboration between the European Organization for Research and Treatment of Cancer (EORTC), Clinical Trial Ireland (CTI), the Canadian Urological Oncology Group (CUOG), the Latin American Cooperative Oncology Group (LACOG), and French UNICANCER Urogenital Tumor Study Group (GETUG).

Additionally, at a preplanned interim analysis the results demonstrated statistically significant overall survival (OS), with a 31% reduction in the risk of death (HR=0.69; 95% CI 0.52-0.90; p=0.0031), with a median OS of 35.0 months (95% CI 28.8-38.9) in the enzalutamide arm compared to 42.3 months (95% CI 36.8-49.1) for XOFIGO plus enzalutamide.¹ The study will continue to the final OS analysis. XOFIGO is the first and only alpha emitting radiopharmaceutical that treats bone metastases in mCRPC approved by the U.S. Food and Drug Administration (FDA).

“PEACE III is the first major Phase III trial to combine an ARPI with radiopharmaceutical that showed statistical significance in meeting the primary endpoint,” said Denis Lacombe, Chief Executive Officer, EORTC. “The EORTC is proud to be at the forefront of this groundbreaking trial, helping to redefine the development of clinical trials and supporting patient care for difficult to treat diseases.”

The results were consistent with the established safety profile of XOFIGO, although authors noted the importance of administering bone protective agents (BPAs) to avoid fractures. Following the release of the ERA-223 results, the PEACE III study was amended in March 2018 making BPAs mandatory at the monthly skeletal-related-event dose. The observed reduction in fractures following this amendment underlined the importance of using a BPA in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastasis also in the era of ARPI’s.⁴ Grade 3 or higher treatment emergent adverse events (TEAE) were recorded in 65.6% of patients in the combination arm compared to 55.8% of patients who received enzalutamide alone.¹ The most frequent Grade 3 or higher TEAEs were hypertension (34%), fatigue (6%), fracture (5%), anemia (5%), and neutropenia (5%).¹ Fractures (either treatment-emergent or post-treatment, symptomatic or pathologic, or with or without BPA use) were reported in 24.3% of patients in the combination arm and 13.4% of patients in the enzalutamide arm.¹ These results demonstrate the potential for this combination to be a new treatment option for patients with mCRPC and bone metastases who have experienced disease progression on androgen deprivation therapy (ADT).

“There remains an unmet patient need for people living with metastatic castration-resistant prostate cancer who have bone metastases,” said Christine Roth, Global Head of Product Strategy and Commercialization at Bayer’s Pharmaceuticals Division. “The PEACE III trial underscores our dedication to advancing therapies for patients with prostate cancer and exploring the full potential of XOFIGO.”

The trial is supported by Astellas and Pfizer who manufacture enzalutamide (Xtandi) in collaboration with Bayer.

About PEACE III (EORTC GUCG-1333)

The PEACE III trial is an international, randomized, open-label, Phase III trial designed to investigate the efficacy and safety of XOFIGO in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. A total of 446 patients were randomized 1:1 to receive either XOFIGO 55 kBq/kg as an intravenous injection monthly for six cycles in combination with enzalutamide 160mg orally daily or enzalutamide 160mg orally daily.

The primary endpoint was radiological progression-free survival (rPFS) by investigator assessment. Key secondary endpoints included overall survival (OS), time to subsequent systemic treatment, pain progression, and symptomatic skeletal event.

This trial was a collaboration with several cancer cooperative groups: EORTC, CTI, CUOG, LACOG, and GETUG.

About Xofigo^® (radium-223 dichloride) Injection²

Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Important Safety Information for Xofigo^® (radium-223 dichloride) Injection

Warnings and Precautions:

• Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the
  
  Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo.
  
  
  
  Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure
  
  

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care

• Concomitant Use With Chemotherapy: Safety and efficacy of concomitant
  
  chemotherapy with Xofigo have not been established. Outside of a clinical trial,
  
  concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

• Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of Xofigo in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established

• Embryo-Fetal Toxicity: The safety and efficacy of Xofigo have not been established in females. Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo

Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

Fluid Status: Dehydration occurred in 3% of patients on Xofigo and 1% of patients on

placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia

Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo

Secondary Malignant Neoplasms: Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial

Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the Xofigo group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy

Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%).

Please see the full Prescribing Information for Xofigo (radium Ra 223 dichloride).

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

About Bayer

Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2023, the Group employed around 100,000 people and had sales of 47.6 billion euros. R&D expenses before special items amounted to 5.8 billion euros. For more information, go to www.bayer.com.

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This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

References

1. Tombal. B., et al. Enzalutamide plus Radium-223 in Metastatic Castration-Resistant Prostate Cancer: Results of the EORTC 1333/PEACE-3 trial. Annals of Oncology. May 30, 2025. DOI: 10.1016/j.annonc.2025.05.011
2. Gillessen, S., 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. European Society of Medical Oncology 2025 (ESMO) LBA1. September 9, 2024.
3. Xofigo^® (radium-223 dichloride) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, December 2019.
4. Gillessen S, et al. Decrease in Fracture Rate with Mandatory Bone-protecting Agents in the EORTC 1333/PEACE-3 Trial Comparing Radium-223 Combined with Enzalutamide Versus Enzalutamide Alone: A Safety Analysis. Eur Urol. 2025 Mar;87(3):285-288. 

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