Combo Disappoints in Metastatic, Castration-Resistant Prostate Cancer

Jennifer Smith

February 12, 2021

Combining the tyrosine kinase inhibitor saracatinib with docetaxel does not benefit patients with metastatic, castration-resistant prostate cancer (mCRPC), according to researchers.

In a phase 1/2 study, adding saracatinib to docetaxel increased toxicity without improving progression-free or overall survival.

"Although we could safely combine the Src kinase inhibitor saracatinib with docetaxel, it did not show any improvement in outcomes, when compared with docetaxel plus placebo. We therefore do not recommend proceeding to a phase 3 trial," said investigator Robert J. Jones, MD, PhD, of the Institute of Cancer Sciences at the University of Glasgow, Scotland.

Jones presented the phase 1/2 trial results at the 2021 Genitourinary Cancers Symposium (Abstract 107).

He explained that saracatinib targets Src family members, and Src activity is increased during the acquisition of castration resistance and during taxane resistance. Jones and colleagues therefore theorized that saracatinib could be beneficial for patients with mCRPC.

The team tested their theory with the phase 1/2 trial, enrolling patients with mCRPC who had not previously received taxanes or radionucleotides. Jones reported results for 10 patients in the phase 1 portion of the trial and 140 patients in the phase 2 portion.

In phase 1, patients received saracatinib at 50 mg, 125 mg, or 175 mg daily plus docetaxel at 75 mg/m2.

There were no dose-limiting toxicities or pharmacokinetic interactions in these patients, so the phase 2 dose of saracatinib was 175 mg daily.

In phase 2, patients were randomized to receive saracatinib plus docetaxel or placebo plus docetaxel.

Results: Safety and Efficacy

"In terms of efficacy, the trial failed to meet its primary endpoint of demonstrating an improvement in progression-free survival. Indeed, there was a trend toward an improvement in progression-free survival for patients receiving placebo," Jones said. "Similarly, in this key secondary endpoint of overall survival, there was no benefit from the addition of saracatinib. And again, there was a trend toward an improved survival in patients receiving placebo."

The median progression-free survival was 19 weeks with saracatinib and 29 weeks with placebo (adjusted hazard ratio, 1.348).

The median overall survival was 62 weeks with saracatinib and 83 weeks with placebo (adjusted HR, 1.422).

Furthermore, there were no significant differences between the treatment arms for two other efficacy endpoints – maximum absolute change in prostate-specific antigen levels and absolute change in circulating tumor cell count from baseline to cycle three.

However, grade 3 or higher adverse events were more common in the saracatinib arm than in the placebo arm – 59% (41/69) and 41% (29/71), respectively.

The most common grade 3 or higher adverse events (in the saracatinib and placebo arms, respectively) were neutropenia (25% vs. 8%), diarrhea (12% vs. 4%), and fatigue (6% vs. 4%).

This research was funded by the UK National Health Service and Cancer Research UK. Jones disclosed relationships with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, and a number of other companies.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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