Efficacy and Safety of Autologous Dendritic Cell–Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer

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 PARTICIPANTSThe 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 MEASURESThe 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 RELEVANCEIn 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 watch: Dendritic cell (DC)-based immunotherapy for cancer

“…Completed Phase III clinical trials in the field are scarce and thus far have failed to show significant advantage achieved via DC-based vaccines in cancer patients. 204 , 250 The results of other advanced trials that are currently ongoing or recently finished are eagerly awaited, particularly for those cancer-types that have failed to respond to currently approved ICBs.…”

Immunotherapy in Advanced Prostate Cancer—Light at the End of the Tunnel?

“…Despite this initial success, further DC vaccines have failed to succeed [ 108 ]. For example, in the phase 3 VIABLE trial, the addition of autologous DC-based immunotherapy to docetaxel and prednisone did not prolong overall survival compared to chemotherapy alone in mCRPC patients [ 109 ]. In addition, no differences in the secondary efficacy end points (rPFS, time to PSA progression, or skeletal-related events) were reported.…”

Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines

“…We recently published the results of three independent open-label, randomized Phase I/II, II and III clinical studies that compared the efficacy of an autologous DC-based vaccine (DCVAC) delivered in the context of standard of care chemotherapy (SOC) versus SOC alone in patients with advanced non-small cell lung carcinoma (NSCLC; SLU01, NCT02470468), 21 epithelial ovarian cancer (EOC; SOV01, NCT02107937), 22 , 23 or metastatic castration-resistant prostate cancer (mCRPC; SP005, NCT02111577). 24 In these settings, DCVAC was well tolerated and significantly extended the progression-free survival (PFS) and overall survival (OS) of EOC or NSCLC patients. 21 , 22 In mCRPC patients, DCVAC combined with SOC and continued as maintenance treatment showed a favorable safety profile but did not extend OS.…”

“… 21 , 22 In mCRPC patients, DCVAC combined with SOC and continued as maintenance treatment showed a favorable safety profile but did not extend OS. 24 …”

“…Of these, 787 were assigned to DCVAC and 395 to placebo. 24 Patients in both arms received SOC, and DCVAC was continued as maintenance therapy. In SLU01 (NCT02470468), 112 patients with advanced NSCLC were randomized to one of three arms between January 2015 and November 2016.…”