End of the Road for Immune Checkpoint Inhibitors in Prostate Cancer?

Adding an immune checkpoint inhibitor (ICI) to chemotherapy for advanced prostate cancer failed to improve survival as compared with chemotherapy alone, according to final results from a large randomized trial.

Men with metastatic castration-resistant prostate cancer (mCRPC) lived 19-20 months whether they received docetaxel plus pembrolizumab (Keytruda) or placebo. The addition of pembrolizumab did not improve overall survival (OS) in patients with PD-L1-positive tumors as compared with the overall study population. The negative outcome mirrored that of an interim analysis that showed no difference in radiographic progression-free survival (rPFS), the primary endpoint.

The trial lacked statistical power to perform hypothesis testing in biomarker-defined subgroups, leaving unanswered the question of whether the combination could improve outcomes in select subsets, reported Daniel Petrylak, MD, of Yale Cancer Center in New Haven, Connecticut, and co-authors in the Journal of Clinical Oncology (JCO).

“New efficacious therapeutic options for mCRPC remain an unmet need,” the authors wrote in conclusion. “Real-world data indicate that the median OS of patients with newly diagnosed mCRPC is <30 months in the United States and Europe, and the most recent progress has occurred in the hormone-sensitive setting. Next-generation studies should investigate novel agents and combinations for this disease.”

The trial is the latest in a string of negative studies evaluating ICIs in combination with proven life-prolonging drugs, noted the author of an accompanying editorial. In both hormone-sensitive and castration-resistant populations, studies have produced no clear rPFS or OS benefits.

“This now raises the question, if there is no evidence of clinical benefit, why do we keep doing costly phase II and phase III trials with these agents especially when combinations do not appear to work?” asked Susan F. Slovin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.

An abundance of preclinical evidence supports synergistic action between docetaxel and ICIs. Nonetheless, the question of whether true synergy exists remains.

A recent study using meta-analysis and sample testing sought to define synergy between ICI and other cancer agents in kidney cancer. Although the study produced evidence supporting synergy, Slovin pointed to a systematic review showing that “favorable preclinical data ultimately translated to >50 clinical trials that used ‘promising’ to describe results, albeit no level 1 evidence to support their use prevailed.”

Other factors could explain the lack of synergy observed to date, including effects of radiation therapy and concomitant use of drugs known to reduce ICI efficacy, such as steroids and antibiotics.

“Considering the prevailing negativity of multiple trials with ICI combinations, should we continue these studies?” Slovin continued. “These trials are not just another trial, but a negative study informs about how to go forward with future studies or to stop because of futility. This study provides a rationale to keep such studies in progress.”

In a separate brief commentary, JCO associate editor Andrea Necchi, MD, of the University of Milan, called for the field to move on from studies that broadly apply ICI combinations in prostate cancer.

“Taxane chemotherapy is unable to sensitize prostate cancer to immune checkpoint inhibitors, resulting in another negative trial with immunotherapy in prostate cancer,” Necchi wrote. “Further trials with immune checkpoint inhibitors in unselected patients should be discouraged.”

Petrylak and co-authors reported the final analysis of KEYNOTE-921, an international, phase III randomized trial to compare docetaxel plus placebo or pembrolizumab in men with mCRPC previously treated with an androgen receptor pathway inhibitor. The trial had dual primary endpoints: rPFS by blinded independent review and OS.

Data analysis included 1,030 randomized patients, and the study represented an older population (median age 71). About 54% had prior abiraterone (Zytiga) and 45% had previously received enzalutamide (Xtandi). About half of the patients had bone-only metastatic spread, and about 70% had PD-L1-negative tumors.

An interim analysis showed a median rPFS of 8.6 months with pembrolizumab versus 8.3 months with placebo representing a non-significant 15% reduction in the hazard ratio (95% CI 0.71-1.01). A preliminary analysis of OS showed no difference between treatment groups. Subgroup analyses showed no substantive differences, including metastatic sites and PD-L1 status.

At final analysis, 53.4% of patients in the pembrolizumab arm had died, as had 55.9% in the placebo arm. The data showed median OS of 19.6 months with pembrolizumab and 19.0 months with placebo (HR 0.92, 95% CI 0.78-1.09). Results were generally consistent across subgroups.

The PD-L1 combined positive score continued to be updated from interim to final analysis, resulting in slightly more PD-L1-positive patients in the pembrolizumab arm. In the PD-L1-positive subgroup, median OS was 19.8 months with pembrolizumab versus 14.9 months with placebo (HR 0.71, 95% CI 0.51-0.98). Median OS in PD-L1-negative patients was 19.6 months in the pembrolizumab arm and 20.8 months in the placebo group.

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