Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial

Abstract

Importance: DCVAC/PCa is an active cellular immunotherapy designed to initiate an immune response against prostate cancer.

Objective: To evaluate the efficacy and safety of DCVAC/PCa plus chemotherapy followed by DCVAC/PCa maintenance treatment in patients with metastatic castration-resistant prostate cancer (mCRPC).

Design, setting, and participants: The VIABLE double-blind, parallel-group, placebo-controlled, phase 3 randomized clinical trial enrolled patients with mCRPC among 177 hospital clinics in the US and Europe between June 2014 and November 2017. Data analyses were performed from December 2019 to July 2020.

Interventions: Eligible patients were randomized (2:1) to receive DCVAC/PCa (add-on and maintenance) or placebo, both in combination with chemotherapy (docetaxel plus prednisone). The stratification was applied according to geographical region (US or non-US), prior therapy (abiraterone, enzalutamide, or neither), and Eastern Cooperative Oncology Group performance status (0-1 or 2). DCVAC/PCa or placebo was administered subcutaneously every 3 to 4 weeks (up to 15 doses).

Main outcomes and measures: The primary outcome was overall survival (OS), defined as the time from randomization until death due to any cause, in all randomized patients. Survival was compared using 2-sided log-rank test stratified by geographical region, prior therapy with abiraterone and/or enzalutamide, and Eastern Cooperative Oncology Group performance status.

Results: A total of 1182 men with mCRPC (median [range] age, 68 [46-89] years) were randomized to receive DCVAC/PCa (n = 787) or placebo (n = 395). Of these, 610 (81.8%) started DCVAC/PCa, and 376 (98.4%) started placebo. There was no difference in OS between the DCVAC/PCa and placebo groups in all randomized patients (median OS, 23.9 months [95% CI, 21.6-25.3] vs 24.3 months [95% CI, 22.6-26.0]; hazard ratio, 1.04; 95% CI, 0.90-1.21; P = .60). No differences in the secondary efficacy end points (radiological progression-free survival, time to prostate-specific antigen progression, or skeletal-related events) were observed. Treatment-emergent adverse events related to DCVAC/PCa or placebo occurred in 69 of 749 (9.2%) and 48 of 379 (12.7%) patients, respectively. The most common treatment-emergent adverse events (DCVAC/PCa [n = 749] vs placebo [n = 379]) were fatigue (271 [36.2%] vs 152 [40.1%]), alopecia (222 [29.6%] vs 130 [34.3%]), and diarrhea (206 [27.5%] vs 117 [30.9%]).

Conclusions and relevance: In this phase 3 randomized clinical trial, DCVAC/PCa combined with docetaxel plus prednisone and continued as maintenance treatment did not extend OS in patients with mCRPC and was well tolerated.

Trial registration: ClinicalTrials.gov Identifier: NCT02111577.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Beer reported receiving research funding paid to institution from Sotio during the conduct of the study; and receiving grants to institution from Alliance Foundation Trials, Astellas Pharma, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Endocyte/Advanced Accelerator Applications, Freenome, Grail, Harpoon Therapeutics, Janssen Research & Development, Medivation, Theraclone Science/OncoResponse, and Zenith Epigenetics; personal fees for consulting from Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Constellation, Grail, Janssen, Myovant Sciences, Pfizer, Sanofi, and Clovis Oncology; and owning stock in Arvinas and Salarius Pharmaceuticals outside the submitted work. Dr Oudard reported receiving personal fees for board membership, honoraria, and consulting from Sotio during the conduct of the study; and receiving personal fees for board membership, honoraria, and consulting from Sanofi, Janssen, Bayer, Ipsen, and Takeda outside the submitted work. Dr Khoo reported receiving personal fees and nonfinancial support from Accuray, Astellas, Bayer, and Boston Scientific and nonfinancial support from Janssen outside the submitted work. Dr Stenzl reported receiving grants from Chiltern International GmbH during the conduct of the study. Dr A. Hussain reported trial sponsorship from Sotio, which provided funding to the institution during the conduct of the study; serving as a consultant for Bayer and Merck; serving on an advisory board for Aveo Pharmaceuticals; sponsored clinical trials from Clovis, Roche, Constellation, Memorial Sloan Kettering Cancer Center, and Calithera; and receiving grants from Medical University of South Carolina outside the submitted work. Dr Sousa reported trial sponsorship from Sotio during the conduct of the study; and receiving personal fees from Janssen, Bayer, Servier, Bristol Myers Squibb, and Merck Sharp & Dohme outside the submitted work; and being site lead investigator in other pharmaceutical companies’ clinical trials: Taiho Oncology, Astellas Pharma Global Development, Eisai, Nektar Therapeutics, Janssen, Bayer, Pfizer, Servier, Roche, Merck Sharp & Dohme, Bristol Myers Squibb, Boston Biomedical, and Exelixis. Dr Bahl reported receiving grants to institution from Sanofi and Janssen and personal fees from Astellas, Bayer, and Janssen outside the submitted work. Dr Bartunkova reported receiving personal fees from Sotio and being a minority shareholder during the conduct of the study; in addition, Dr Bartunkova has a patent for dendritic cell vaccine manufacturing using high hydrostatic pressure issued. Dr Spisek reported having a patent for high hydrostatic pressure for cancer immunotherapy issued. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

aA total of 136 patients did not start DCVAC/PCa (119 because of production failures and 19 for other reasons). bBecause of a protocol violation, 4 patients in the placebo group received DCVAC/PCa; these 4 patients were included in the DCVAC/PCa group in the safety analysis set. AE indicates adverse event; ICF, informed consent form.

Figure 2.. Kaplan-Meier Estimates of Overall Survival, Efficacy Analysis Set

Median overall survival (95% CI): DCVAC/PCa, 23.9 (21.6-25.3) months; placebo, 24.3 (22.6-26.0) months. Stratified log-rank test: hazard ratio, 1.04 (95% CI, 0.90-1.21). Tick marks indicate censored data.

Figure 3.. Kaplan-Meier Estimates of Overall Survival in Abiraterone and/or Enzalutamide-Naive Patients, Efficacy Analysis Set

Median overall survival (95% CI): DCVAC/PCa, 26.7 (25.2-28.8) months; placebo, 25.7 (23.8-28.3) months. Stratified log-rank test: hazard ratio, 0.94 (95% CI, 0.78-1.13). Tick marks indicate censored data.