Bone is the most common site of metastatic involvement in breast and prostate cancer. Bone metastases can cause complications defined as skeletal-related events. Phase 3 studies have shown higher activity for prevention of skeletal-related events with denosumab (a RANKL antibody) when compared to zoledronic acid, a bisphosphonate. With Denosumab, severe hypocalcemia had been reported in up to 5% of patients. Additionally, dose/ time-dependent increase of risk of osteonecrosis of the jaw had been demonstrated as well. Prior trials have shown that de-escalated doses of bisphosphonates have similar efficacy in preventing skeletal-related events.
The primary objective of the presented study was to determine whether 120 mg of Denosumab every 12 weeks was non-inferior to 120 mg every four weeks. The primary endpoint was time to first on-trial symptomatic skeletal event. Interestingly, the study was sponsored not by pharma companies, but in part by an umbrella organization of Swiss health insurance companies (Santesuisse). The benefit for the insurers in funding this trial included the fact that it is cost-neutral, it has a potential cost reduction if the trial will show non-inferiority, and less toxicity is associated with reduced secondary costs. Lastly, the insurers can develop a track record for supporting modern, patient-friendly trials, which will result in their involvement in future trials, becoming more common.
The design of the REDUSE trial is demonstrated in Figure 1. Eligibility criteria for the trial included patients with castrate-resistant prostate cancer, with more than three bone metastases, with a performance status of 0-2, corrected serum calcium >=2 mmol/l and <=3 mmol/l. The patients must not have had a history of osteonecrosis, and could not have a prior history of denosumab or bisphosphonates therapy for bone metastases.
Figure 1 – REDUSE Trial Design:
The secondary endpoints of the trial included toxicity (focused on hypocalcemia), time to first and subsequent on trial symptomatic skeletal event, overall survival, quality of life, skeletal morbidity period rate, skeletal morbidity rate, health economic analysis, and bone turnover markers.
In this presentation, data from a pre-planned interim analysis of 282 patients with castrate-resistant prostate cancer and >=1 dose of denosumab was shown. Upon reviewing the results of the interim analysis, the Independent Data Monitoring Committee (IDMC) recommended that the trial continue, focusing on hypocalcemia.
Dr. Gillessen moved on to discuss the results of the interim analysis. A total of 272 patients completed the four-week induction phase and were included in the analysis. Following the induction phase, 28.7% of patients had hypocalcemia, with only 2.2% and 0.4% having grade 3 and grade 4 hypocalcemia, respectively. When assessing the results of the comparison between both arms, after 16 weeks 40.2% of the patients in the four-week arm compared to 20.3% of the patients in the 12-week arm had hypocalcemia (Figure 2). An interesting point that Dr. Gillessen mentioned is that when compared to the original comparison of Denosumab to zoledronic acid (1), the hypocalcemia rate in the present trial was three times higher (39.7% vs. 13%).
Figure 2 – Hypocalcemia by grade, treatment period and arm:
The proportion of patients developing hypocalcemia over time was higher for arm A (four-week treatment) compared to arm B (12-week treatment), as seen in figure 3.
Figure 3 – First occurrence of hypocalcemia by period:
Dr. Gillessen concluded the presentation of this trial stating the hypocalcemia occurs at a rate of almost 40% when using standard four-weekly Denosumab treatments, much more frequent than previously reported. Hypocalcemia was considerably lower in the 12-weekly arm compared to the four-weekly arm. Lastly, following 64 weeks, it was shown to be quite rare to develop hypocalcemia.
We look forward to the final results of this trial.
Presented by: Silke Gillessen, MD, Professor and Chair in Genitourinary Oncology Systemic Therapy Research at The University of Manchester and The Christie NHS Foundation Trust, Co-founder of the Advanced Prostate Cancer Consensus Conference (APCCC)
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA
1. Fizazi K. et al.Fizazi, K., Carducci, M., Smith, M., Damião, R., Brown, J., & Karsh, L. et al. (2011). Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. The Lancet, 377(9768), 813-822. doi: 10.1016/s0140-6736(10)62344-6 2011