Atezolizumab plus enzalutamide does not improve OS or cancer control vs enzalutamide in metastatic CRPC

Atezolizumab, given in combination with enzalutamide, did not show improvement in overall survival (OS) or cancer control compared with enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC), resulting in early termination of the phase III IMbassador250 study.

“The IMbassador250 trial is the first phase III trial to investigate a checkpoint immunotherapy combination in mCRPC. The addition of atezolizumab to enzalutamide did not improve OS or cancer control in mCRPC, and programmed death-ligand 1 [PD-L1] expression did not identify a population of patients who benefited from the combination therapy. Biomarker studies are ongoing and may provide further insight into these findings,” said investigator Dr Christopher Sweeney from the Dana-Farber Cancer Institute, Boston, US, who presented the results at the AACR 2020 Virtual Meeting I.[Sweeney C, et al, AACR 2020, abstract CT014]

In the trial, 759 patients (Eastern Cooperative Oncology Group performance status [ECOG PS] 0–1; median age, 70.0 years) with mCRPC that progressed on prior abiraterone, or who had failed or were ineligible for or refused a taxane regimen were randomized (1:1) to receive a combination of atezolizumab (1,200 mg intravenously Q3W) plus enzalutamide (160 mg QD), or enzalutamide alone.

At baseline, visceral metastasis was present in 35 percent of all patients, in which 11 percent had liver metastasis. In terms of PD-L1 expression, 72 percent, 15 percent and 3 percent had immune cell [IC] 0, IC 1/2/3 and IC 2/3, respectively.

At a median follow-up of 11 months, the trial’s primary endpoint of OS was not significantly improved with atezolizumab plus enzalutamide vs enzalutamide alone (median, 15.2 months vs 16.6 months; hazard ratio [HR], 1.2; 95 percent confidence interval [CI], 0.91 to 1.37; p=0.28).

Similarly, atezolizumab-enzalutamide yielded no significant OS improvement across patient subgroups, regardless of their PD-L1 expression, presence or absence of visceral metastasis, prior docetaxel use, and prior local therapy.

Secondary endpoints of radiographic progression-free survival (rPFS) and time to prostate-specific antigen (PSA) progression were also not significantly improved with atezolizumab-enzalutamide vs enzalutamide alone (rPFS, 4.2 months vs 4.1 months; HR, 0.90; 95 percent CI, 0.75 to 1.07) (time to PSA progression, 2.8 months vs 2.8 months; HR, 1.04; 95 percent CI, 0.87 to 1.24).

Assessment of disease response revealed an objective response rate (ORR) of 14 percent vs 7 percent in the atezolizumab-enzalutamide group vs the enzalutamide group, with a median duration of response of 12.4 months vs not estimable. Confirmed PSA response was achieved in 26 percent of patients in the atezolizumab-enzalutamide group vs 24 percent of those in the enzalutamide group.

The safety profile of the atezolizumab-enzalutamide combination was consistent with the known safety profiles of the individual agents. Grade 3/4 adverse events of special interest (AESIs) occurred in 11.5 percent vs 1.3 percent of patients in the atezolizumab-enzalutamide vs enzalutamide group, while 3 patients (<1 percent) in the atezolizumab-enzalutamide group experienced grade 5 AESIs. The most commonly reported grade 3/4 AEAIs were any rash (7.5 percent vs 6.6 percent) and hypothyroidism (<1 percent vs 2.1 percent). The grade 5 AESIs reported with atezolizumab-enzalutamide were myositis, pneumonitis, and myasthenic syndrome, experienced by one patient each.