Abstract 2723
Background
The bone-targeting agents (BTAs) denosumab and bisphosphonates (BPs) are widely used in the supportive care of patients (pts) with CRPC and bone metastases. We present data on pts treated with radium-223 dichloride (Ra-223) with or without a concomitant BTA in an international EAP.
Methods
This was a prospective single-arm phase IIIb study of CRPC pts with symptomatic or asymptomatic bone metastases (no visceral disease) recruited from 14 countries. Pts received Ra-223 50 kBq/kg [55 kBq/kg after NIST update] (iv injection) every 4 weeks for 6 cycles. Co-primary endpoints were safety and overall survival (OS). Exploratory analyses investigated the effects of concomitant denosumab (no BPs) or BPs (no denosumab) on OS and symptomatic skeletal events (SSE).
Results
696 pts received at least one Ra-223 cycle. Of those, 127 (18%) pts were treated with concomitant denosumab (no BPs) and 435 (63%) without concomitant BTAs. Key baseline characteristics are reported in pts treated with Ra-223 with or without a concomitant BTA (Table). Median OS (mOS) and median time to first SSE (mSSE) were longer in pts treated with Ra-223 and denosumab versus pts without a concomitant BTA (Table). While key baseline characteristics in pts treated with Ra-223 and denosumab were similar to pts treated with Ra-223 and BPs (no denosumab, 125 [18%] of 696), adding BPs to Ra-223 did not appear to improve mOS. However, mSSE was prolonged in pts receiving Ra-223 and BPs versus pts who received Ra-223 without a concomitant BTA (Table).
Concomitant treatment with Ra-223 (administered after the first injection of Ra-223, or before the study and continued after the first Ra-223 injection)
| Denosumab | BPs | No denosumab /no BPs | |
|---|---|---|---|
| N = 127 | N = 125 | N = 435 | |
| Baseline characteristics | |||
| ECOG PS, n (%) | |||
| 0 | 58 (46%) | 55 (44%) | 144 (33%) |
| 1 | 55 (43%) | 54 (43%) | 234 (54%) |
| ≥2 | 14 (11%) | 16 (13%) | 57 (13%) |
| Pain, n (%) | 123 | 122 | 413 |
| Mild | 75 (61%) | 72 (59%) | 218 (53%) |
| Moderate-severe | 19 (15%) | 24 (20%) | 113 (27%) |
| None | 29 (24%) | 26 (21%) | 82 (20%) |
| ALP (U/L), n | 127 | 125 | 433 |
| Median | 121.0 | 137.0 | 168.0 |
| PSA (µg/L), n | 127 | 124 | 433 |
| Median | 91.2 | 118.5 | 174.6 |
| Efficacy outcome | |||
| Overall survival | |||
| Median, months | NR | 12.7 | 13.4 |
| 95% CI | NA | 10.9–NA | 11.7–NA |
| Hazard ratio (95% CI) | 0.630 (0.431–0.922) | 0.846 (0.584–1.226) | - |
| Time to first SSE | |||
| Median, months | 17.0 | NR | 15.8 |
| 95% CI | 17.0–17.5 | NA | 10.9–19.1 |
| Hazard ratio (95% CI) | 0.761 (0.493–1.173) | 0.498 (0.294–0.845) | - |
NR/A = not reached/available.
Conclusions
In this EAP, pts treated with Ra-223 and a concomitant BTA appeared to have longer time to first SSE than those treated without a concomitant BTA. However, improvement in OS with a BTA was observed with denosumab but not with BPs. Prospective randomized controlled studies are required to confirm the benefit of this specific treatment combination in metastatic CRPC.
Clinical trial identification
ClinicalTrials.gov NCT01618370
Legal entity responsible for the study
Pharmaceutical Division of Bayer
Funding
Pharmaceutical Division of Bayer
Disclosure
F. Saad: Grants, personal fees and non-financial support from Bayer, Amgen, Janssen, and Astellas, during the conduct of the study.
A. Heidenreich: Grants and personal fees from Bayer during the conduct of the study; grants and personal fees from Astellas and Sanofi Aventis, personal fees from Amgen, Dendreon, Ferring, Hexal, IPSEN, Janssen-Cilag, Pfizer, and Takeda; outside the submitted work.
D. Heinrich: Grant from Bayer, during the conduct of the study; personal fees from Bayer, Amgen, Astellas, Sanofi, and Johnson & Johnson, outside the submitted work.
J.M. O'Sullivan: Advisory boards for: Bayer, Astellas, Sanofi.
J. Carles: Scientific advisory board membership/consultancy: Johnson & Johnson, Astellas, Bayer, Amgen, Pfizer, BMS; Speakers Bureau: Bayer, Johnson & Johnson.
M. Wirth: Personal fees from Apogepha, Astellas, Bayer, Janssen-Cilag, Merck, Roche, and Sanofi-Aventis outside the submitted work.
K. Miller: Advisory board membership: Bayer.
J. Gratt: Personal fees from Bayer Healthcare during the conduct of the study.
M. Seger-van Tol: Employment: Bayer.
S. Nilsson: Participated in Bayer Healthcare advisory boards and as speaker in scientific meetings.
S. Gillessen: Advisory Boards (compensated): Astellas, Bayer, Curevac, Dendreon, Janssen Cilag, Janssen Diagnostics, Millennium, Novartis, Orion Pharma, Pfizer, Sanofi Aventis. Speakers Bureau (without honorarium): Bayer. Pending patent application: WO 2009138392 A1.
All other authors have declared no conflicts of interest.