Xtandi for Metastatic Castration-Resistant Prostate Cancer

  • The recent results from the PEACE III trial, presented at the 2024 European Society for Medical Oncology (ESMO) Annual Meeting, offer promising insights into the treatment of mCRPC with bone metastases.
  • The trial highlighted the potential of combining enzalutamide (brand name Xtandi), an androgen receptor pathway inhibitor (ARPI), with radium-223 (Ra223 – Brand name Xofigo), a bone-targeting radiopharmaceutical.
  • The combination therapy significantly increased median radiographic PFS from 16.4 months (enzalutamide alone) to 19.4 months.
  • An interim analysis showed a median overall survival of 42.3 months for the combination therapy versus 35.0 months for enzalutamide alone.

Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge, particularly when patients no longer respond to androgen deprivation therapy (ADT). The emergence of new therapeutic strategies is crucial for improving patient outcomes.

The recent results from the PEACE III trial, presented at the 2024 European Society for Medical Oncology (ESMO) Annual Meeting, offer promising insights into the treatment of mCRPC with bone metastases, highlighting the potential of combining enzalutamide (brand name Xtandi), an androgen receptor pathway inhibitor (ARPI), with radium-223 (Ra223 – Brand name Xofigo), a bone-targeting radiopharmaceutical.

Xtandi has provided much hope in treating prostate cancer in recent years.

“Xtandi, it’s a quadruple threat because it has four unique indications for prostate cancer,” Dr. David Wise, a genitourinary medical oncologist with NYU Langone Health, told SurvivorNet in early 2024. It can be used to treat non-metastatic castration-sensitive disease, metastatic castration-sensitive disease, non-metastatic castration-resistant disease, and metastatic castration-resistant disease. 

As all who work in the prostate cancer space know, bone metastases are unfortunately prevalent in mCRPC, leading to significant morbidity and mortality. Traditional treatment options have focused on symptom management and prolonging survival, but the need for more effective therapies remains — and the PEACE III Trial is showing a lot of promise.

The PEACE III Trial: Design and Collaborations

The PEACE III trial is an international, randomized Phase 3 study designed to evaluate the efficacy of combining enzalutamide with Ra223 in asymptomatic or mildly symptomatic mCRPC patients with bone metastases.

The trial is a collaborative effort involving several cancer cooperative groups, including Clinical Trial Ireland (CTI), the Canadian Urological Oncology Group (CUOG), the Latin American Cooperative Oncology Group (LACOG), and the French UNICANCER cooperative group (GETUG).

Over eight years, the trial enrolled 439 patients who were randomized to receive either the combination of enzalutamide and Ra223 (n = 215) or enzalutamide alone (n = 224). Patients included in the study had not previously received either agent, had no known visceral metastases, and maintained castration levels of testosterone.

Key Findings from the PEACE III Trial

Improved Progression-Free Survival (PFS)

  • The combination therapy significantly increased median radiographic PFS from 16.4 months (enzalutamide alone) to 19.4 months.
  • This represents a 31% improvement (HR, 0.69; P = 0.0009).
  • At 24 months, 45% of patients in the combination group were progression-free compared to 36% in the enzalutamide group.

Overall Survival Benefit

  • An interim analysis showed a median overall survival of 42.3 months for the combination therapy versus 35.0 months for enzalutamide alone.
  • This 7.3-month improvement suggests a considerable survival advantage (HR, 0.69; P = 0.0031).
  • Due to non-proportional hazards, further analysis is required to confirm and characterize the overall survival benefit fully.

Delayed Time to Next Systemic Treatment

  • The addition of Ra223 extended the time to the next systemic treatment.
  • At 24 months, only 30% of patients in the combination group had started a new systemic therapy compared to nearly 51% in the enzalutamide group (HR, 0.57; P < 0.0001).

Safety and Toxicity Profile

  • The combination therapy was generally well-tolerated.
  • Grade 3-5 drug-related adverse events occurred in 28% of patients receiving the combination versus 19% with enzalutamide alone.
  • Common adverse events included fatigue, fractures, anemia, neutropenia, and hypertension.
  • Importantly, the study highlighted the need for bone-protecting agents to mitigate fracture risk.

Clinical Implications and Expert Opinions

The PEACE III trial is the first major Phase 3 study to suggest that combining an ARPI with another approved medication (Ra223) significantly improves overall survival in mCRPC patients. Previous attempts to combine ARPIs with other agents, such as PARP inhibitors or other ARPIs, failed to demonstrate a significant survival benefit in the intent-to-treat population.

Prof. Silke Gillessen, the study chair, remarked on the synergy observed between Ra223 and enzalutamide, emphasizing that the added toxicity is manageable. Prof. Bertrand Tombal, co-chair of the study, highlighted that PEACE III provides a new role for Ra223 earlier in the disease course, which is promising news for patients.

Denis Lacombe, CEO of the European Organisation for Research and Treatment of Cancer (EORTC), stated that the trial has the potential to significantly improve patient outcomes, aligning with EORTC’s mission to conduct impactful research.

Considerations for Clinical Practice

Bone-Protecting Agents

The mandatory use of bone-protecting agents during the trial was crucial in reducing the risk of fractures.

Clinicians should consider incorporating agents like bisphosphonates or denosumab when prescribing this combination to mitigate skeletal-related events.

Monitoring for Adverse Events

Regular monitoring for hypertension is necessary, as enzalutamide is associated with an increased risk.

Awareness and early intervention can manage hypertension effectively, ensuring patients can continue therapy without significant complications.

Patient Selection

The trial included patients who had not received prior ARPIs or Ra223.

Further research is needed to determine the efficacy of this combination in patients who have previously been treated with ARPIs.

Impact of New Therapies

The treatment landscape for mCRPC is evolving, with newer agents like Lutetium-177 PSMA showing promise.

The role of Ra223 may need reevaluation in the context of these emerging therapies. Combination strategies involving radioligand therapies may offer additional benefits but require further investigation.

Future Directions

The promising results from the PEACE III trial open avenues for further research:

  • Long-Term Outcomes: Continued follow-up is necessary to confirm the overall survival benefit and assess long-term safety
  • Combination with Other Therapies: Exploring the efficacy of combining Ra223 with other ARPIs or novel agents may provide additional benefits.
  • Personalized Medicine: Identifying biomarkers that predict response to Ra223 could optimize patient selection and improve outcomes.

Dr. Rodrigo C. Leão Edelmuth is a board certified digestive surgeon at Hospital Israelita Albert Einstein in São Paulo, Brazil.

He holds his General Surgery and Digestive Surgery degree from São Paulo University Medical School.

He underwent a postgraduate course on Surgical Leadership at Harvard Medical School and a Research Fellowship in the Department of Surgery at Weill Cornell Medicine in New York.

Dr. Edelmuth is member of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and of the Society for Surgery of the Alimentary Tract (SSAT). In 2022 he received the SAGES Career Development Award.

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