Despite this, there are relatively limited treatment options for patients with bone only disease: while radium-223 (R223) has demonstrated overall survival (OS) benefit, but objective clinical responses to R223 or the anti-PD1 checkpoint inhibitor (CPI) pembrolizumab are infrequent. In a plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Choudhury and colleagues present the results of a phase II study to assess the safety of the combination and differences in immune cell infiltrate in bone biopsies (bx) and preliminary clinical activity of R223 + pembrolizumab vs. R223 alone, based on the rationale that R223 may increase the immunogenicity of mCRPC to bone and increase the activity of CPI.
The authors recruited men with mCRPC to bone with no visceral metastases or lymph nodes > 2 cm. They further required that men have an ECOG performance score of 0 or 1, Hgb ≥ 9 g/dL, and no prior R223 or CPI therapy. Patients underwent bone biopsy at screening and at 8 weeks per protocol.
Included patients were randomized 2:1 to receive R223 55 kBq/kg q4wks + pem 200 mg q3wks (Arm A) or R223 55 kBq/kg q4wks alone (Arm B with stratification according to alkaline phosphatase ≥220 vs. < 220 U/L and high vs. low volume bony metastases, according to CHAARTED criteria.
The authors assessed the primary endpoint of a difference in CD4+ and CD8+ T-cell infiltrate in 8 week vs. baseline biopsy. Secondarily, they assessed safety/tolerability, radiographic progression-free survival (rPFS), OS, and exploratory endpoints including PSA response and rate of symptomatic skeletal events (SSEs).
If restaging after 3 doses of R223 showed at least stable disease, pts in Arm A continued pembrolizumab monotherapy until progressive disease (PD). At the time of disease progression, R223 was resumed if no new visceral metastases were present. Patients continued therapy until there was clinical or radiologic evidence of progressive disease, unacceptable toxicity or completion of six R223 doses.
The authors assessed the primary endpoint of a difference in CD4+ and CD8+ T-cell infiltrate in 8 week vs. baseline biopsy. Secondarily, they assessed safety/tolerability, radiographic progression-free survival (rPFS), OS, and exploratory endpoints including PSA response and rate of symptomatic skeletal events (SSEs).
The authors enrolled 45 patients, of whom 42 received study therapy (29 Arm A, 13 Arm B) and were eligible for analysis. 21 pts in Arm A and 5 in Arm B had evaluable paired bone biopsies (baseline and 8 weeks). Median fold-change of proportion of CD4+ T-cells/total cell count from baseline to 8 weeks was larger in arm A (0.90, range 0.0-26.6) than arm B (0.40, 0.0-13.0) though this was not significant (P = 0.87). Similarly, changes in CD8+ cells were not significant between arm A (median 0.67, 0.0-40.4) and arm B (0.40, 0.1-28.8) (P = 0.77).
Grade 3 toxicity (including pneumonitis, diarrhea, and AST elevations) were more common in arm A (3 patients) compared with arm B (0). Based on preliminary clinical data, median OS was 16.9 months (12.7-NR) in Arm A and 16.0 months (9.0-NR) in Arm B.
Notably, SSEs and pathologic fractures were less common in patients in arm A (38% and 0%, respectively) than in arm B (54% and 23%, respectively).
The authors conclude that, among evaluable patients, the combination of radium-223 and pembrolizumab did not increase rates of CD4+ or CD8+ T-cell infiltration, compared to radium-223 alone. Further, in this biomarker unselected population, the combination did not improve clinical outcomes to a degree necessary to support the use of this approach.
Presented by: Atish Dipankar Choudhury, MD, Ph.D., Dana-Farber Cancer Institute
Co-Authors: Lucia Kwak, Alexander Cheung, Abhishek Tripathi, Amanda Fredericks Pace, Eliezer Mendel Van Allen, Kerry L. Kilbridge, Xiao X. Wei, Bradley Alexander McGregor, Mark Pomerantz, Christopher Sweeney, Mary-Ellen Taplin, Heather Jacene, Glenn Bubley, Lauren C Harshman, Lawrence Fong, Rupal Satish Bhatt
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021