SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.
Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as Bicalutamide (CASODEX®), Nilutamide (NILANDRON®) and Flutamide (EULEXIN®) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPIs), which include Abiraterone (ZYTIGA®), Enzalutamide (XTANDI®), Apalutamide (ERLEADA®) and Darolutamide (NUBEQA®).
For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Pathway Inhibitors (ARPIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.
Radium Ra 223 dichloride (XOFIGO®) is a bone seeking alpha particle emitter, and by virtue of its chemical similarity to calcium is preferentially taken up by the bone and forms complexes with bone mineral hydroxyapatite, in areas where there is increased bone turnover such as bone metastases. Ra-223 induces double stranded DNA breaks resulting in antitumor effects and has a very short range in tissues (around 2 and 10 cells), quickly losing energy, compared to beta or gamma radiation. The end result is less damage to the adjacent healthy tissues. Further, unlike its historical counterpart Ra-226 which was first isolated by Madame Curie, Ra-223 has a short half life of 11.4 days and rapidly decays, preventing significant radiation exposure. Ra-223 in a randomized, double-blind, Phase III trial (ALSYMPCA study) improved Overall Survival in patients with CRPC with bone metastases (mCRPC).
Enzalutamide is an orally administered, second-generation, anti-androgen, with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway and was designed to overcome acquired resistance to first-generation nonsteroidal anti-androgens.
The PEACE-3 trial is a pivotal double-blind, randomized Phase III study exploring whether combining Enzalutamide with Ra-223 dichloride provides enhanced efficacy over Enzalutamide monotherapy in mCRPC with bone metastases. As a cooperative effort led by EORTC, CTI, CUOG, LACOG, and UNICANCER, the trial enrolled 426 mCRPC patients (N=426) from 12 countries between 2015 and 2023. Participants were required to have bone metastases, be asymptomatic or mildly symptomatic, and be naïve to prior treatments with Enzalutamide, Ra-223, or other specific anti-androgen therapies (Apalutamide or Darolutamide). Patients were randomized in a 1:1 to receive either Enzalutamide monotherapy (Standard of Care) at 160 mg taken orally once daily, or a combination of Enzalutamide 160 mg daily plus Ra-223 administered at 55 kBq/kg IV every four weeks, for six cycles. Patients were stratified by factors including country, baseline pain scores, prior use of Docetaxel, previous treatment with Abiraterone, and use of bone-protecting agents (which became mandatory after an early protocol amendment). The decision to require bone-protecting agents was driven by fracture rate concerns seen in the ERA-223 study, which had paired Ra-223 with Abiraterone and showed increased fracture risks without these bone-protecting agents. The median age of patients was 70 years and both treatment groups were well balanced. About 30% had received Docetaxel, with fewer than 5% previously treated with Abiraterone. About 42-44% of patients had ten or more bone lesions, and about 37% had elevated alkaline phosphatase levels, an indicator of high bone turnover. The Primary endpoint was radiological Progression-Free Survival (rPFS). Secondary endpoints include Overall Survival (OS), Time to subsequent systemic anti-neoplastic therapy, Time to pain progression, and Time to first symptomatic skeletal event. The median follow-up duration was 42.2 months.
The combination of Enzalutamide and Ra-223 showed a statistically significant improvement in rPFS. Patients in the combination arm had a median rPFS of 19.4 months, compared to 16.4 months for enzalutamide alone (HR=0.69; P=0.0009). Interim results demonstrated a 31% reduction in mortality risk in the combination arm, with median OS extending from 35 months with Enzalutamide alone to 42.3 months with the combination (HR=0.69; P=0.0031). Although nonproportional hazards were observed, necessitating a continued final OS analysis, these interim findings strongly suggest the potential survival benefit with this combination therapy.
Patients on the combination therapy had a significantly longer period before needing subsequent systemic treatments, with a 43% lower risk of starting a new therapy compared to those on Enzalutamide alone (HR=0.57; P< 0.0001). At the two-year mark, 51% of patients in the Enzalutamide-only group required additional treatments, compared to 30% in the combination group. There were no significant differences between the groups in time to pain progression or the onset of Symptomatic Skeletal Events (SSEs), which include fractures and spinal cord compression.
The combination of Enzalutamide plus Ra-223 was well tolerated, although it led to a slight increase in Grade 3 or higher adverse events (28%) compared to 19% in the Enzalutamide monotherapy group. Approximately 30% of patients in both groups experienced hypertension, though severe cases were more frequent in the combination arm. Other common side effects included fatigue and cytopenias. The safety protocol of the study was adjusted to include mandatory bone-protecting agents such as Denosumab or Zoledronate and baseline DEXA scans, contributing to fewer symptomatic skeletal events. Over 80% of patients received these agents during the trial, likely mitigating the risk of fractures and other bone-related adverse effects seen in similar trials.
It was concluded from the PEACE-3 trial that adding 6 cycles of Ra223 to Enzalutamide as first-line therapy for mCRPC patients, significantly improved radiological Progression-Free Survival. A preplanned interim analysis showed a statistically significant Overall Survival benefit favoring the Enzalutamide plus Ra-223 combination, although further analysis will address long-term survival and Quality of Life outcomes.
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. Gillessen S, Choudhury A, Saad F, et al. Annals of Oncology, Volume 35, S1254. September 2024.
