Multiple Trials Explore Radium-223 Combinations for mCRPC

Silke Gillessen, MD

Clinical trials are now assessing how to best use radium-223 (Xofigo) in combination with androgen inhibitors, following the rapid approval of several agents for men with castration-resistant prostate cancer (CRPC).

In the first of these studies, a phase III being conducted by the European Organisation for Research and Treatment of Cancer (EORTC), single-agent enzalutamide (Xtandi) is being compared with radium-223 plus enzalutamide for men with asymptomatic or mildly symptomatic bone metastatic CRPC (NCT02194842). Additionally, this same approach is being examined in a phase II study conducted by the All Ireland Cooperative Oncology Research Group (NCT02225704).

"The combination of enzalutamide and radium-223 could attack two important features of metastatic castration-resistant prostate cancer," said the principal investigator of the phase III study, known as PEACE III, Silke Gillessen, MD, from the Cantonal Hospital of St. Gallen in Switzerland. "One of these is an adaptation by cancer cells so that they continue to stimulate the androgen receptor pathway, thus simulating cancer growth/regrowth. The other is their ability to grow in places where bone remodeling has been disrupted."

Within the United States, an open-label phase IIa study is exploring radium-223 with either abiraterone acetate (Zytiga) or enzalutamide for men with bone metastatic CRPC (NCT02034552). Moreover, an international phase III study is exploring abiraterone plus radium-223 in men with bone-metastatic CRPC prior to the administration of chemotherapy (NCT02043678).

"For men with advanced disease, the objective is to control the disease while maintaining quality of life," PEACE III study chair Bertrand Tombal, MD, PhD, of the Cliniques Universitaires Saint-Luc in Brussels, Belgium, said in a statement. "Androgen deprivation therapy is generally administered initially, but often patients become resistant to this treatment."

The FDA approved radium-223 in May 2013 as a treatment for men with symptomatic CRPC that had spread to the bones but not to any other organs. This decision was based on findings from the pivotal phase III ALSYMPCA trial, which showed a median overall survival (OS) of 14 months with radium-223 versus 11.2 months with placebo (HR, 0.70; P = .00185).

The rationale for the combination trials stemmed from an expanded access program (EAP) for radium-223, which enrolled in the United States. The EAP was an open-label phase II study for men with CRPC and bone metastases. In those who received radium-223 with concurrent enzalutamide (n = 15), the median OS was 10.7 months. In the concurrent abiraterone arm (n = 25), the median OS was not estimable.

In the small number of patients who received concurrent abiraterone or enzalutamide, radium-223 had a safety profile similar to that observed in the overall expanded-access population. The most common treatment-emergent grade 3/4 adverse events were anemia (16% with abiraterone, 13% with enzalutamide), thrombocytopenia (4%, 0%), and back pain (0%, 13%).

"The EAP really gave us some hypothesis generating ideas, in particular around combinations that could be utilized with radium-223: enzalutamide and abiraterone," Joe O'Sullivan, MD, head of the radiation oncology and prostate cancer clinical research groups at Northern Ireland Cancer Centre, told OncLive. "Already, in the real world use of radium-223, clinicians are combining these therapies so it would be beneficial to have a better understanding of if there is a synergistic relationship between these therapies."

Abiraterone acetate is as an androgen biosynthesis inhibitor targeted against CYP17, which is expressed in testicular, adrenal, and prostatic tumor tissues. Enzalutamide works by binding to the androgen receptor, which blocks the androgen-signaling pathway. Radium-223 is an alpha particle emitting radiopharmaceutical that works by mimicking calcium, causing it to be taken up by bone metastases.

"Enzalutamide prevents androgens from binding to their receptor, and radium-223, by mimicking calcium, targets areas of bone metastases," said Gillessen. "The fact that the safety profiles of both drugs for the most part do not overlap and both treatments are generally well tolerated makes them interesting combination partners. Furthermore radium-223 offers an additional mechanism of action when combined with enzalutamide that is approved for this indication, which makes them a potentially effective combination, too."

The primary endpoint for the phase III PEACE-III trial is focused on radiographic progression-free survival. The study hopes to enroll 560 patients. In the other phase III study exploring radium-223 plus abiraterone, the primary outcome measure is focused on symptomatic skeletal event-free survival. This trial plans to enroll 800 patients. The smaller phase II studies are focused on bone scan response and safety.