Keytruda Plus Xtandi Showed No Improvements in Prostate Cancer Subset

The addition of Keytruda (pembrolizumab) to Xtandi (enzalutamide) showed no improvements in radiographic progression-free survival (rPFS; time from treatment until new cancer lesions are seen on scans) and overall survival (OS; time from treatment until death from any cause), when comparing Xtandi alone in patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from the KEYNOTE-641 study presented at the ESMO Congress 2023.

As a result, the primary end points of OS and rPFS were not met and the study was stopped for OS futility at the first interim analysis.

“Future studies should focus on patient selection and the identification of positive predictive markers of response, more so than treating all comers, which several studies have shown has not really worked here or they acknowledge it,” Dr. Julie N. Graff, Oregon Health & Science University Knight Cancer Institute, explained in a recent presentation of the data.

The median follow-up time at first prespecified interim analysis was 27.6 months. At that time, the median OS was 24.7 months with placebo plus Xtandi, compared with 27.3 months with placebo plus Xtandi.

Further, the 12-month OS rates in the pembrolizumab and placebo arms were 77.9% vs 77.6%, respectively, whereas 18-month rates were 63.6% vs 63.0%.

Subgroup analyses—stratified by age, race, region, ECOG performance status (which determines how, if at all, disease affects patients’ independence), prior docetaxel for metastatic hormone-sensitive prostate cancer, prior abiraterone therapy, metastases at baseline and PD-L1 status — also did not demonstrate an OS benefit with Keytruda and Xtandi over placebo and Xtandi.

Median rPFS with Keytruda plus Xtandi was 10.4 months vs 9.0 months with placebo.

Similar to OS, there was no rPFS benefit seen across the prespecified subgroup analysis.

The investigators evaluated time to initiation of first subsequent anticancer therapy (the time from randomization to the earlier of start date of the first subsequent anti-cancer therapy, TFST) as a secondary end point of the study. Median TFST with Keytruda vs placebo was 13.2 months and 12.6, respectively.

Additionally, objective response rate (ORR) was served as a secondary end point. The ORR with Keytruda plus Xtandi was 32.3%, including 17 complete responses (complete disappearance of disease), of which five of those patients received prior Zytiga (abiraterone; 2.2%); compared with an ORR of 23.9% with placebo plus Xtandi, including six CRs (2.7%), of which two of those patients received prior Zytiga (0.9%). The disease control rate in each respective arm was 50% and 46.0%.

“Interestingly, complete response was higher with (Keytruda) plus (Xtandi). However, it's not clear what the molecular changes were to the tumor that might have allowed this,” Graff noted.

Across the Keytruda and placebo arms, grade 3 or higher side effects occurred in 55.8% and 41.0% of patients, respectively, whereas grade 3 or higher treatment-related side effects were seen in 31.2% and 10.8% of patients, and 30.9% and 7.4% of patients had immune-mediated side effects and infusion reactions.

The most common side effects occurring in at least 5% of patients in the Keytruda and placebo arms included fatigue (22.9% vs 19.8%, respectively), rash (18.7% vs 4.0%), itching (11.9% vs 4.5%), nausea (11.1% vs 8.5%), decreased appetite (10.9% vs 9.0%), diarrhea (10.7% vs 7.1%), weakness/lack of energy (9.9% vs 2.9%), hypothyroidism (9.9% vs 2.9%), maculopapular rash (6.8% vs 0.6%), joint pain/stiffness (6.5% vs 4.2%), anemia (5.4% vs 3.7%) and hypertension (4.4% vs 5.2%).

In the randomized, double-blind phase 3 KEYNOTE-641 study, investigators randomized patients to receive either 200 mg Keytruda intravenously every three weeks (621 patients) or placebo every three weeks (623 patients) plus 160 mg oral Xtandi every day.

To be eligible for the trial, patients had to have confirmed m CRPC; no prior docetaxel for the disease; had no previously received prior Xtandi, Erleada (apalutamide), or Nubeqa (darolutamide); had an ECOG performance status of 0 or 1, indicating that they can perform all of their daily tasks with little to no help; and had a tissue sample available for biomarker assessment. Prior treatment with Zytiga (abiraterone) was permitted.

At baseline, patients in the Keytruda group were at a median age of 71 years (median, 45-91). The majority had an ECOG performance status of 0 (58.3%; can independently perform all daily tasks). In total, 85.7% of patients had bone metastases, 12.2% has visceral metastases and 3.5% had liver metastases. Regarding prior treatment received, 60.5% were given abiraterone and 29.0% were administered docetaxel. To finalize the study, most patients were PD-L1 negative (70.4%).

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