Details of Study That Led to Radium-223 Restriction in Europe

Alexander M. Castellino, PhD

October 20, 2018

MUNICH — Details of the ERA 223 clinical trial that led to a restriction in Europe of the use of the radiopharmaceutical radium-223 dichloride (Ra-223; Xofigo, Bayer) have now been presented here at the European Society for Medical Oncology (ESMO) 2018 Congress. 

The trial was unblinded early after a signal of a higher fracture rate and increase in deaths.  

ERA 223 was conducted in men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The higher fracture rate was seen in the group who received the radiopharmaceutical in combination with abiraterone acetate (Zytiga, Janssen Oncology) and prednisone/prednisolone (AAP); the fracture rate was 26%, compared with 10% for those receiving AAP alone.

As a result of this finding, in July 2018, as reported by Medscape Medical News, the European Medicines Agency (EMA) aligned with its Pharmacovigilance Risk Assessment Committee (PRAC) and recommended restricting the use of Ra-223 to patients who had two previous treatments for metastatic prostate cancer with bone metastases or to those who could not use any other treatment.

The primary endpoint of the trial was symptomatic skeletal event-free survival (SSE-FS) rate, and this was similar for both groups of patients (49% for the combination of Ra-223 and AAP vs 47% for AAP alone). Median SSE-FS was 22.3 months with the combination and 26.0 months for AAP alone.

Median overall survival (OS) was 30.7 months with the combination and 33.3 months with AAP alone, and the difference was also not significant.  

However, in its announcement about restricting the indication for Ra-223, the EMA noted that patients on the combination died 2.6 months earlier on average than those in the AAP group.

The EMA also noted that Ra-223 is only approved for use in patients with symptoms, and that the ERA 223 trials were conducted in patients with no or only mild symptoms.

Why the trial did not meet its endpoint, how the results of ERA 223 impact the use of Ra-223 in clinical practice, and whether the EMA decision to restrict the use of Ra-223 was premature were issues addressed in an enlightening discussion by Daniel Heinrich, MD, of the Akershus University Hospital in Lørenskog, Norway.

Understanding Why ERA 223 Failed

Heinrich explained that in setting up the study, the statistical assumption made was that the median SSE-FS for patients in the control arm (AAP + placebo) would be 21 months. The combination was expected to yield a 39% improvement, which corresponded to a median SSE-FS of 29.2 months. He surmised that the expectation of a 39% improvement was set from the ALSYMPCA trial, which showed a hazard ratio (HR) of 0.7 for Ra-223 compared with placebo.  

He shared data from the COU-AA-302 and COU-AA-301 studies in which AAP was compared with prednisone and highlighted that in those studies, the median OS for AAP was 34.7 months and the median time to first skeletal event was 25.0 months, respectively. "In this regard, the control arm in ERA 223 did as expected," Heinrich said.

However, in the COU-AA-302 study, the Kaplan-Meier curves for OS for AAP and prednisone overlapped for 12 months and separated only later, he pointed out.

Excess toxicity in ERA 223 was the reason for the failed study, Heinrich suggested. The trial used a drug that targeted the bone (Ra-223) and added a drug with toxicity towards the bone (abiraterone). Indeed, he showed data that bone fracture rates were high with the combination and occurred early in the study — as early as 6 to 12 months.

He pointed out that in all other trials with other agents (eg, AAP, enzalutamide) used in combination with hormonal therapy in mCRPC the fracture rate was higher than the control.

"The trial never had a chance of being positive," Heinrich said. "The combination of Ra-223 and AAP cannot be recommended as first-line treatment for patients with mCRPC," he added.

Implications for Using Ra-223 Daily in the Clinic

Heinrich further discussed the ramifications of ERA 223 for the use of Ra-223 in daily clinical practice. The concomitant addition ("lay-up") of Ra-223 to AAP, or for that matter enzalutamide, has never been tested in clinical trials, he said. ERA 223 does not provide any evidence to recommend or discourage such an approach, he suggested.

He highlighted the amended EMA indication — the use of Ra-223 as monotherapy or in combination with androgen-deprivation therapy in the third-line setting of mCRPC. The EMA also issued a contraindication for Ra-223 in combination with AAP and indicated that it should not be started in the first 5 days following the last AAP dose nor should any systemic therapy be provided to patients for 30 days following the last dose of Ra-223.

Heinrich highlighted the EMA observations that 46% of the patients in the ERA 223 study were mildly symptomatic and that a subgroup analysis of patients with ≤ 6 (vs > 6) bone metastases showed more fractures and no benefits compared with placebo.

"The EMA disregarded the overall survival advantage seen with radium-223 in the ALYSYMPCA study, which promoted the original indication, and restricted the indication for all men with mCRPC, not just a subset of patients," Heinrich told Medscape Medical News.

He noted that no other agency, including the US Food and Drug Administration (FDA), has amended the original indication for Ra-223, which is for use in patients with symptomatic mCRPC with bone metastases. That indication was approved on the basis of data from the phase 3 ALSYMPCA study, which showed an overall survival (OS) benefit, as noted in the approval of the drug by the FDA in 2013.

"We need to communicate the benefits of Ra-223 to patients who are provided this treatment option," he said.

"In daily clinical practice, we would never give Ra-223 and AAP as first-line therapy when we see patients such as those enrolled in the ERA 223 study," Heinrich told Medscape Medical News.

"The EMA should rethink and revoke the indication change," he commented.

Heinrich highlighted the finding from the ERA 223 trial that lower fracture rates that were seen in patients receiving bone health agents (BHAs) such as bisphosphonates or denosumab, and endorsed their use not only with Ra-223 but other agents as well. "What will have to change is the use of BHAs in our patients," Heinrich said.

Details of the ERA 223 Results   

At the meeting, Matthew Smith, MD, of the Massachusetts General Hospital Cancer Center, Boston, presented the results of the ERA 223 study.

The rationale for evaluating the combination of Ra-223 and AAP was based on observations of the nonoverlapping toxicities seen for each of the drugs, improved OS and radiographic progression-free survival (rPFS), and a post-hoc analyses of an early access, open-label, single-arm phase 3b study, which suggested a survival benefit with Ra-223 in combination with AAP or enzalutamide, Smith noted.

Patients with bone-predominant mCRPC who were mildly symptomatic or asymptomatic and had received no prior chemotherapy for CRPC were randomized to receive the combination of Ra-223 and AAP (n = 401) or AAP plus matching placebo (n = 405).

The primary endpoint was time from randomization to first SSE or death from any cause. Any SSE was defined as use of external beam radiation therapy (EBRT) to relieve skeletal symptoms, new symptomatic pathological bone fracture, spinal cord compression, or tumor-related orthopedic surgical intervention.

The baseline characteristics were similar across the two groups. Median age was 71 years. Approximately 60% of patients had a Gleason score of 8 or higher; two thirds of patients had more than five bone metastases; BHAs were used in approximately 40% of patients. Median prostate-specific antigen (PSA) was 30 mg/L.

In November 2017, the study was unblinded because the data monitoring committee noted an excess of fractures and death with the combination of Ra-223 and AAP. All patients had completed study-specified Ra-223/placebo treatment prior to unblinding.

With an HR of 1.22 (P = .2636), the SSE-FS was similar across the two groups. Death prior to an SSE was similar across the two groups (74 patients for Ra-223 and AAP vs 73 patients for AAP alone). For patients with SSE as the first event, pathological fractures were seen in twice as many patients receiving the combination (35 patients) than AAP alone (17 patients).

OS was also similar across the two groups, with an HR of 1.195 (P = .128). All other secondary and exploratory endpoints were also not significant across the two groups (eg, rPFS, time to opiate use for cancer pain, time to PSA progression).

Treatment-emergent adverse event rate and serious adverse event rate were also similar across the two groups — except for fracture rates. Grade 3 fractures were seen in 9% of patients receiving the combination and 3% of patients receiving AAP alone.

Fracture events were reviewed by an independent review committee. Of patients receiving the combination with more than one fracture (76 vs 23 for AAP alone), approximately half the fractures were osteoporotic for patients on the combination (37 [49%] vs 4 [4%] for AAP alone). Pathological fractures suggestive of metastases were similar across the groups (25% vs 26% for AAP alone) and traumatic fractures were higher in patients receiving AAP alone (57% vs 36% for Ra-223 and AAP).

A subgroup analysis revealed that patients who received BHA at baseline had a much lower fracture rate — 15% for patients receiving the combination and 7% for patients receiving AAP alone. For patients without BHA use at baseline, fracture rate was 37% for the combination and 15% for AAP alone.

Echoing the sentiments of the discussant, Smith noted that based on data from this study, the concurrent use of Ra-223 and AAP is not recommended.

However, he also said that clinical practice needs to change, and providing BHAs to patients with mCRPC should be part of clinical management. Indeed, after the unblinding, the ERA 223 protocol was amended to allow initiation of BHAs across the arms.

The study was funded by Bayer. Heinrich has reported receiving honoraria and/or being an advisor to AstraZeneca, Bayer, Eisai, IPSEN, Janssen-Cilag, Roche, Astellas, and Bristol-Myers Squibb. His research is also funded by AstraZeneca, Bayer, Janssen-Cilag, Roche, Merck Sharp & Dohme, and Bristol-Myers Squibb.

European Society for Medical Oncology (ESMO) 2018 Congress. Abstract LBA30.

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