Background We hypothesized that Ra223 in combination with enza would induce a higher degree of immune activation and clinical response than enzalutamide alone in patients with mCRPC.
Methods Patients were randomized 2:1 to Arm A (enza + Ra223) or Arm B (enza only). Blood was collected at start of treatment and evaluated by flow cytometry to measure immune activation or exhaustion after ≥3 months on study, and by Luminex for cytokines after 1 month on study. A Kaplan-Meier model was used to calculate survival data. Expression of immune correlatives were log-transformed and analyzed with the Wilcoxon Rank Sum test to detect differences between the two arms.
Results A total of 28 patients were enrolled, whose median age was 68 (57 – 87). 6 are Hispanic (21%) and 2 each are African American or Asian (7%). Median duration of follow up was 8.3 (1.8 – 29.9) months (mo). 9 pts (36%) had visceral metastases. Arm A showed significantly greater increase in PD-L2 expression after treatment compared to Arm B (p = 0.0026). There was otherwise no significant difference between the two arms for flow cytometry markers. Cytokines remained low generally, except for IL10 and TNFa, elevated in 5 and 2 patients, respectively. 9 of 21 (48%) in Arm A had SD or PR as best RECIST response compared to 3 of 9 (33%) in Arm B. PSA response was not different between the arms. Arm A had PFS of 8.8 (3.6 – 29.9+) mo while PFS was 5.3 (3.4 – 12.2+) mo in Arm B. 4 (27%) patients in Arm A and 3 (50%) patients in Arm B stopped treatment due to disease progression. No grade 3 adverse events were observed in either arm and no unexpected toxicities occurred.
Conclusions Although Ra223 with enza did not show increased PD-L1 expression as seen in pre-clinical mouse models treated with Ra223, the combination did significantly induce PDL-2 expression in this study and raise the potential of improved treatment efficacy with the addition of an immune checkpoint inhibitor as suggested in these pre-clinical models.1 Despite the lack of augmentation of humoral response, combination treatment paradoxically showed better clinical response, consistent with prior studies involving Ra223 and Sipleucel-T immunotherapy.2
Acknowledgements The authors thank Bayer for providing funding to perform the clinical trial.
Trial Registration NCT03344211
Vardaki I, Corn P, Gentile E, et al. Radium-223 treatment increases immune checkpoint expression in extracellular vesicles from the metastatic prostate cancer bone microenvironment. Clin Cancer Res 2021; 27: 3253–3264.
Marshall CH, Fu W, Wang H, et al. Randomized Phase II Trial of Sipuleucel-T with or without Radium-223 in Men with Bone-metastatic Castration-resistant Prostate Cancer. Clin Cancer Res 2021; 27: 1623–1630.
Ethics Approval This study was approved by the IRB of the University of Southern California and the IRB of City of Hope.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.