Neal Shore, MD
The combination of radium-223 dichloride (Xofigo) and abiraterone acetate (Zytiga) was associated with significant reductions in bone pain, as well as improvements in quality of life (QOL), in patients with metastatic castration-resistant prostate cancer (mCRPC), according to results of a phase II study.
Overall, pain severity decreased by 35.3% and more than half of patients had at least a 30% reduction of their worst pain. Additionally, half or more of the 31 evaluable patients in the open-label study had threshold-level improvement in multiple measures of QoL, as reported at the 2016 AUA Annual Meeting.
“This is the first prospective trial of radium-223 and abiraterone acetate, and it shows an improvement in quality of life and demonstrates the synergistic benefits of these agents,” Neal Shore, MD, medical director of the Carolina Urologic Research Institute, and colleagues concluded in a poster presentation. “The [quality of life and bone pain] data from this trial suggest the benefits of concomitant use.”
Both radium-223 and abiraterone have FDA-approved indications for mCRPC. Preclinical studies have suggested potential therapeutic synergy with the combination of the 2 agents, providing a rationale for the trial reported by Shore.
Investigators enrolled men with symptomatic mCRPC and metastases limited to bone. Treatment consisted of radium-223 administered every 4 weeks for a total of 6 doses, concurrent abiraterone, and prednisone. Eligible patients had initiated a stable dose of daily abiraterone plus prednisone within 90 days of enrollment or started a stable dose of abiraterone plus prednisone within 30 days of the first radium-223 infusion. Follow-up assessments occurred on day 1 of every treatment cycle.
The data analysis included 36 patients who received at least 1 radium-223 infusion. Efficacy analysis was based on the 31 patients who completed all 6 cycles of combined therapy. The primary endpoint was change in bone pain, as assessed by the Bone Pain Inventory-Short Form, and quality of life as determined by the FACT-P questionnaire.
Secondary endpoints included findings from computed tomography and bone scans, changes in prostate-specific antigen (PSA) and alkaline phosphatase (ALP), need for additional antineoplastic therapy, occurrence of skeletal-related events (SREs), change in ECOG performance status, and safety.
The 36 men had a median age of 75, three-fourths were white, two-thirds had Gleason grade 7-8 disease, and a majority entered with high or complete functionality. Additionally, 44.4% of the patients were receiving narcotic pain medication at enrollment. All patients had received prior hormonal therapy, and most had received 1 or more form of additional therapy, including systemic treatment and radiotherapy.
The primary analysis showed that 18 of 31 (58%) evaluable patients had at least a 30% reduction of worst pain without an increase in the use of analgesic medications. In the subgroup of patients with clinically significant pain at baseline, 84% had a 30% improvement or more in worst pain.
The results also showed that 12 of 31 (39%) patients had clinically meaningful palliation of pain that interfered with daily activities. The figure increased to 50% of patients for the subgroup with clinically significant pain interference at the start of treatment.
An analysis of quality of life data showed that a majority of patients met criteria for minimally important improvement in prostate cancer (80.6%), FACT-P total (64.5%), functional wellbeing (61.3%), trial outcome index (59.9%), physical wellbeing (58.9%), FACT-G (58.9%), and emotional wellbeing (54.8%).
Data on bone scans and ALP suggested additional benefits of the treatment. Investigators found that 19 of 31 (61%) of patients had improvement in bone lesions, and 35% had stable bone lesions, leaving 1 patient with worsening bone scans. ALP response data showed 21 (68%) patients had reductions in serum ALP, 8 (26%) had increased ALP that was still within normal limits, and 2 patients had increased ALP levels that exceeded normal limits.
Analysis of other outcomes showed that 16 of 36 patients reduced their pain medication use. No patient required additional anticancer therapy, and no SREs occurred in any patient. Performance status remained stable throughout the study.
The safety analysis showed that 30 of 36 patients reported 186 adverse events (AEs), which were grade 1/2 severity in all but 7 cases. The most frequent treatment-related AEs were diarrhea (19.4%), nausea (19.4%), and fatigue (16.7%). Six serious AEs occurred, 1 (abdominal pain) of which led to withdrawal from the study. One patient died, but the death was not considered treatment related.
Two additional phase II studies have begun, addressing some of the limitations of the current study: small sample size, lack of long-term follow-up data, and difficulty evaluating PSA changes as eligibility criteria allowed patients to begin abiraterone as far as 90 days in advance of the initial dose of radium-223.
Shore N, Tutrone R, Nordquist L, et al. Open-label phase II study evaluating the efficacy of concurrent administration of radium Ra 223 dichloride and abiraterone acetate in men with castration-resistant prostate cancer patients with symptomatic bone metastases (eRADicAte). Presented at: 2016 American Urological Association Annual Meeting; May 6-10, 2016; San Diego, CA. Abstract LB-S&T-12.
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