It's a Bust: Adding Immunotherapy No Benefit in mCRPC

Neil Osterweil

April 29, 2020

AACR 2020 — No clinical benefit was seen from adding the immune checkpoint inhibitor atezolizumab (Tecentriq, Genentech) to standard treatment with the androgen receptor inhibitor enzalutamide (Xtandi; Astellas Pharma) for men with metastatic castration-resistant prostate cancer (mCRPC).

Median overall survival, the trial's primary endpoint, was numerically but not statistically longer among patients with mCRPC who were randomly assigned to receive treatment with enzalutamide alone, reported lead investigator Christopher J. Sweeney, MBBS, from the Dana-Farber Cancer Institute in Boston.

The finding comes from the phase 3 IMbassador250 trial.

This was "the first phase 3 trial to investigate a checkpoint inhibitor therapy combination in metastatic CRPC. It revealed no evidence of a difference in cancer control between arms, whether it be measured by radiographic progression-free survival or time to PSA [prostate-specific antigen] progression," he said.

Adding insult to injury, the investigators could not identify, on the basis of expression of programmed death ligand–1 (PD-L1), a subpopulation of patients who might have benefited from the combination therapy, and adverse events were more frequent than with enzalutamide alone, Sweeney said.

Sweeney presented the results online during the American Association for Cancer Research (AACR) 2020 virtual meeting.

What Happened?

It sounded good on paper: the clinical rationale for combining an immune checkpoint inhibitor with enzalutamide was that there was evidence that immunotherapy with sipuleucel-T (Provenge, Dendreon Pharmaceuticals) had efficacy in CRPC, and initial investigations with ipilimumab (Yervoy, Bristol-Myers Squibb) that showed an increase in antigen-specific T cells following treatment with sipuleucel-T, Sweeney said.

In addition, there has been evidence that programmed death–1 (PD-1) blockade may have activity following the development of resistance to enzalutamide and that monotherapy with atezolizumab, an inhibitor of PD-1 and PD-L1, was associated with long-term disease control in mCRPC, he added.

However, these new results "indicate that neither anti-PD-1/PD-L1 monotherapy or the anti-PD-1/PD-L1 combination therapy with enzalutamide are likely to provide improved clinical benefit over standard-of-care agents for patients with mCRPC whose disease progressed on prior hormonal therapy and prior chemotherapy," commented Padmanee Sharma, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant.

Discussing why the IMbassador250 trial may have failed, she noted that prostate cancer has few T cells, and therefore targeting PD-1 or PD-L1 would not have much of an effect.

"There are multiple immunosuppressive pathways within the prostate tumor microenvironment, and the PD-1/PD-L1-targeting agents may not sufficiently target all these immunosuppressive pathways," she said.

In addition, "there are few mutations in prostate cancer, and as a result, the effector T cells may not be able to recognize an adequate number of antigens to lead to an antitumor response," Sharma said.

Study Details

The IMbassador250 study was a phase 3, multicenter, randomized, open-label study involving 759 men with metastatic, locally advanced, or incurable CRPC who had experienced disease progression with abiraterone (Zytiga, Janssen), were ineligible or refused a taxane-based regimen, or for whom a taxane regimen had failed.

After stratification on the basis of prior taxane therapy, presence of liver metastases, lactate dehydrogenase levels, and pain severity in the past 24 hours, the patients were randomly assigned to receive either enzalutamide 160 mg daily or the same regimen plus atezolizumab 1200 mg intravenously every 3 weeks. Treatment continued until loss of clinical benefit or unacceptable toxicity.

Median overall survival (OS) was 15.2 months with the combination, compared with 16.6 months for enzalutamide alone, which translated into a hazard ratio for death with the combination of 1.12 (P = .28).

The 12-month OS rates were 60.6% for enzalutamide alone vs 64.7% for the combination.

An analysis of OS by clinical subgroup found no advantage from the combination over enzalutamide alone for prior docetaxel exposure, prior local therapy, measurable disease status, the presence of visceral or nonvisceral metastases, or PD-L1 expression.

Radiographic progression-free survival was 4.2 months with atezolizumab/enzalutamide vs 4.1 months with enzalutamide alone (P = ns). Time to PSA progression was 2.8 months in each arm.

Among patients with measurable disease at baseline, the overall response rates were 14% in the combination group and 7% in the group that received enzalutamide alone. Two patients in the combination group and one in the enzalutamide-only group had complete responses.

Grade 3 or 4 treatment-related adverse events (AEs) occurred in 28% of patients who received the combination, vs 10% who received enzalutamide alone. Seven patients in the combination arm and one in the enzalutamide arm died from treatment-related causes. Treatment-related serious AEs were also more frequent with the combination (14% vs 3%), and AEs that led to discontinuation of any treatment component occurred in 14% of patients in the combination arm, vs 6% in the enzalutamide-alone arm.

The study was sponsored by F. Hoffman-La Roche. Enzalutamide was provided by Astellas and Pfizer. Sweeny has advisory or consulting roles and/or has received research funding from the companies. Sharma has consulting roles, has engaged in advisory board activities, or owns stock in for various companies, not including the sponsors.

American Association for Cancer Research (AACR) 2020: Abstract CT014. Presented April 27, 2020.

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