Abiraterone acetate and prednisone/prednisolone (AAP) improves progression-free survival and overall survival (OS) in men with mCRPC. Ra-223 increases OS and decreases symptomatic skeletal events (SSEs) in men with mCRPC and bone metastases. We evaluated concurrent treatment with AAP and Ra-223.
This phase 3, double-blind, placebo (PBO)-controlled trial randomised asymptomatic/mildly symptomatic men with chemotherapy-naïve mCRPC and bone metastases in a 1:1 ratio of AAP + Ra-223 or AAP + PBO. Bone health agents (BHAs [bisphosphonates or denosumab]) were only allowed in pts receiving them at baseline. The primary endpoint was SSE-free survival (SSE-FS).
806 pts were randomised (401 to AAP + Ra-223; 405 to AAP + PBO); 39% and 42% of pts were receiving BHAs at baseline in the AAP + Ra-223 and AAP + PBO arms, respectively. The trial was unblinded early after more fractures and deaths were observed in the AAP + Ra-223 arm. All pts had completed study-specified Ra-223/PBO treatment prior to unblinding. At the primary analysis, median SSE-FS was 22.3 mo (95% CI 20.4−24.8) with AAP + Ra-223 and 26.0 mo (95% CI 21.8−28.3) with AAP + PBO (HR 1.122, 95% CI 0.917−1.374; p=0.2636). Median OS was 30.7 mo (95% CI 25.8−not estimable) with AAP + Ra-223 and 33.3 mo (95% CI 30.2−41.1) with AAP + PBO (HR 1.195, 95% CI 0.950−1.505; p=0.1280). Other secondary/exploratory endpoints are shown in the Table. Fractures occurred in 29% and 11% of pts in the AAP + Ra-223 and AAP + PBO arms, respectively. In pts receiving BHAs, 15% and 7% experienced a fracture in the AAP + Ra-223 and AAP + PBO arms, respectively, vs 37% and 15% without BHAs.
|AAP + Ra-223 |
|AAP + PBO |
|HR (95% CI)|
|Additional secondary endpoints|
|rPFS (central review), median (95% CI), months||11.2 (9.1–11.8)||12.4 (10.8–14.5)||1.152 (0.960–1.383)|
|Time to cytotoxic chemotherapy, median (95% CI), months||29.5 (26.5–35.7)||28.5 (23.7–NE)||1.033 (0.816–1.308)|
|Time to opiate use for cancer pain, median (95% CI), months||19.0 (14.4–23.2)||22.6 (18.0–25.7)||1.126 (0.921–1.378)|
|Overall confirmed PSA response, n/N (%)||287/396 (72)||267/401 (67)||–|
|Time to PSA progression, median (95% CI), months||9.6 (8.2–10.8)||9.0 (7.9–10.1)||0.937 (0.792–1.108)|
|Overall confirmed ALP response, n/N (%)||218/398 (55)||104/402 (26)||–|
|Time to ALP progression, median (95% CI), months||7.4 (7.1–7.9)||6.8 (5.3–8.4)||1.083 (0.918–1.276)|
|Time to deterioration in health-related quality of life*, |
median (95% CI), months
|9.5 (6.9–12.0)||10.5 (8.3–13.0)||1.079 (0.865–1.345)|
|*As reported in the safety population (AAP + Ra-223 N=392, AAP + PBO N=394) using the NCCN-FACT FPSI-17 physical disease-related symptoms subscale score measured during the treatment period. ALP: alkaline phosphatase; NE: not estimable; PSA: prostate-specific antigen; rPFS: radiological progression-free survival.|
Concurrent AAP + Ra-223 treatment did not improve SSE-FS or OS and led to a higher fracture rate. Based on these results, we do not recommend Ra-223 in combination with AAP.
Clinical trial identification
Medical writing support was provided by Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer