Abstract 2971
Background
Identifying a reliable marker of efficacy for radium-223 dichloride (Ra-223) would aid in the clinical management of mCRPC patients (pts). In exploratory analyses of mCRPC pts with symptomatic bone metastases treated with Ra-223 in the ALSYMPCA trial, OS was significantly longer in pts with a confirmed decline in ALP levels from baseline at week 12, compared with pts without a confirmed ALP decline. Here, we present data on ALP dynamics and OS and time to first symptomatic skeletal event (SSE) in pts treated with Ra-223 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, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and OS. Exploratory analyses investigated whether a confirmed decline (any magnitude) in ALP levels was associated with OS and time to first SSE.
Results
696 pts received at least one Ra-223 cycle. Of those, 398 (57%) pts had a confirmed decline in ALP and 298 (43%) had no confirmed ALP decline. Key baseline characteristics are shown (Table). More pts with a confirmed ALP decline (374, 94%) received 5–6 Ra-223 injections than those with no ALP decline (99, 33%). Hazard ratios (HR) for confirmed ALP decline at week 12 vs no decline suggest a strong association of ALP decline with both longer OS (HR 0.299, 95% CI 0.227–0.395) and longer time to first SSE (HR 0.474, 95% CI 0.340–0.662) (Table).
| Confirmed ALP decline | No confirmed ALP decline | |
|---|---|---|
| N = 398 | N = 298 | |
| Baseline characteristics | ||
| ECOG PS, n (%) | ||
| 0 | 170 (43%) | 91 (31%) |
| 1 | 189 (47%) | 159 (53%) |
| ≥2 | 39 (10%) | 48 (16%) |
| Paina, n (%) | 380 | 287 |
| Mild | 217 (57%) | 153 (53%) |
| Moderate-severe | 79 (21%) | 79 (28%) |
| None | 84 (22%) | 55 (19%) |
| ALP (U/L), n | 398 | 296 |
| Median | 149.0 | 148.5 |
| PSA (µg/L), n | 398 | 295 |
| Median | 117.2 | 202.0 |
| Hemoglobin, g/dL | ||
| Median | 12.4 | 11.8 |
| Efficacy outcome | ||
| Overall survival | ||
| Events, n (%) | 86 (22%) | 124 (42%) |
| Median, months | NR | 10.0 |
| 95% CI | NA | 8.6–11.5 |
| Hazard ratiob | 0.299 | |
| 95% CI | 0.227–0.395 | |
| Time to first SSE | ||
| Events, n (%) | 76 (19%) | 67 (22%) |
| Median, months | 17.5 | NR |
| 95% CI | 17.0–18.1 | NA |
| Hazard ratiob | 0.474 | |
| 95% CI | 0.340–0.662 |
NR/A, not reached/available. aMeasured from the brief pain inventory short form.bCalculated from Cox proportional hazards model.
Conclusions
In this EAP, which is relevant for pts currently treated in clinical practice, decline in ALP was associated with longer OS and time to first SSE.
Clinical trial identification
ClinicalTrials.gov NCT01618370
Legal entity responsible for the study
Pharmaceutical Division of Bayer
Funding
Pharmaceutical Division of Bayer
Disclosure
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.
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.
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.
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. Serger-van Tol: Employment: Bayer.
S. Nilsson: Participated in Bayer Healthcare advisory boards and as speaker in scientific meetings.
F. Saad: Grants, personal fees and non-financial support from Bayer, Amgen, Janssen, and Astellas, during the conduct of the study.
All other authors have declared no conflicts of interest.