Late Breaking Abstract – ESMO 2018 Treatment with a Combination of XOFIGO® and ZYTIGA® NOT Recommended in Metastatic Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. Over 90% of the patients with metastatic prostate cancer have bone metastases, and the tumor burden, is an independent predictor of death in this patient population. Agents such as ZOMETA® (Zoledronic acid) and XGEVA® (Denosumab) can prevent or delay Skeletal Related Events (SRE’s) and External Beam Radiation Therapy (EBRT) is often utilized to treat symptomatic SRE’s. EBRT can however damage the bone marrow in the radiated field, resulting in cytopenias, and consequently can potentially preclude patients from receiving cytotoxic chemotherapy.

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. XOFIGO® 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 Ra-226 which was first isolated by Madame Curie, XOFIGO® has a short half life of 11.4 days and rapidly decays, preventing significant radiation exposure.

XOFIGO® in a randomized, double-blind, Phase III trial (ALSYMPCA study) improved overall survival in patients with CRPC (Castrate Resistant Prostate Cancer) with bone metastases. Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17A. ZYTIGA® along with Prednisone in a double-blind, randomized, Phase III study (COU-AA-302 trial) significantly improved Overall Survival compared with Prednisone alone, in patients with chemotherapy-naive metastatic CRPC. This formed the basis for this present study.

ERA 223 is a randomized, double-blind, placebo controlled, Phase III trial in which 806 patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic Castration Resistant Prostate Cancer with at least 2 bone metastases were randomly assigned in a 1:1 to ZYTIGA® plus concurrent XOFIGO® (N=401) versus ZYTIGA® plus matching placebo (N=405). Bone Health Agents (BHAs) (Bisphosphonates or XGEVA®) were only allowed in patients receiving them at baseline, and 39% of patients in the ZYTIGA® plus XOFIGO® and 42% in the ZYTIGA® plus placebo arms were receiving BHAs at baseline. The median age was 71 years in both treatment groups. The Primary endpoint was Symptomatic Skeletal Event-Free Survival (SSE-FS), defined as freedom from the use of External Beam Radiation to relieve symptomatic skeletal events, new symptomatic pathologic bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or death. Secondary endpoints included Overall Survival, radiological Progression Free Survival (rPFS), time to cytotoxic chemotherapy, and time to opiate use for cancer pain. This study was unblinded prematurely due to more fractures and deaths in the ZYTIGA® plus XOFIGO® group. All patients had completed study-specified XOFIGO® /placebo treatment prior to unblinding. The treatment was however continued, and the protocol was amended to allow BHAs in patients who were not taking them at baseline.

At the primary analysis, it was noted that there was no significant difference between the two treatment arms for the Primary endpoint of Symptomatic Skeletal Event-Free Survival. The median Symptomatic Skeletal Event-Free Survival was 22.3 months in the ZYTIGA® plus XOFIGO® group versus 26 months in the ZYTIGA® plus placebo group (P=0.263). The Secondary endpoint of Overall Survival (OS) was 30.7 months with ZYTIGA® plus XOFIGO® and 33.3 months with ZYTIGA® plus placebo (P=0.128) and this was not significantly different. Fractures occurred in 29% of patients in the ZYTIGA® plus XOFIGO® group and 11% of patients in the ZYTIGA® plus placebo group respectively. Patients who were taking BHAs still sustained more fractures in the XOFIGO® containing arm. Baseline use of BHAs however was associated with lower fracture rates in both treatment groups. In patients receiving BHAs, 15% and 7% experienced a fracture in the ZYTIGA® plus XOFIGO® and ZYTIGA® plus placebo arms respectively, versus 37% and 15% without BHAs.

It was concluded that concurrent ZYTIGA® plus XOFIGO® treatment did not improve Symptomatic Skeletal Event-Free Survival or Overall Survival but on the contrary led to a higher fracture rate. Based on these results, the authors recommended against the use of XOFIGO® in combination with ZYTIGA®. ERA 223: A phase 3 trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Smith MR, Parker CC, Saad F, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA30.