Pembrolizumab Plus Enzalutamide/ADT Fails to Improve rPFS in mHSPC

The addition of pembrolizumab (Keytruda) to enzalutamide (Xtandi) and androgen deprivation therapy (ADT) did not improve radiographic progression-free survival (rPFS) vs placebo plus enzalutamide and ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to data from the phase 3 KEYNOTE-991 trial presented at the 2023 ESMO Congress.

Findings showed that at a median follow-up of 21.1 months (range, 14.8-32.0), patients treated with pembrolizumab plus enzalutamide and ADT (n = 626) experienced 12- and 18-month rPFS rates of 79.8% and 72.6%, respectively, compared with 81.8% and 76.2% in patients treated with placebo plus enzalutamide and ADT (n = 625). The median rPFS was not reached (NR) in the pembrolizumab vs NR in the placebo arm (HR, 1.20; 95% CI, 0.96-1.49; P = .95).

Overall survival (OS) served as a dual primary end point with rPFS; however, per the study’s statistical plan, OS was not formally tested. Data did show that the 12- and 24-month OS rates were 91.7% and 80.6%, respectively, for the pembrolizumab arm compared with 94.1% and 82.6%, respectively, for the placebo arm. The median OS was NR in both arms (HR, 1.16; 95% CI, 0.88-1.53).

“The randomized phase 3 KEYNOTE-991 study showed that the addition of pembrolizumab to enzalutamide and ADT did not significantly improve the primary endpoint of rPFS for participants with novel hormonal agent [NHA]–naive mHSPC,” lead study author Christian Gratzkem, MD, of the University Hospital Freiburg, in Freiburg, Germany, wrote in a presentation of the data. “No formal statistical testing occurred for OS, although OS results appeared similar between treatment arms… Secondary efficacy end points also did not appear improved with pembrolizumab plus enzalutamide.”

The phase 3 trial enrolled patients with a confirmed mHSPC who had 2 or more verified bone lesions or visceral disease and no prior NHA therapy. Patients who received no more than 6 cycles of docetaxel treatment were permitted to enroll if it was given no more than 2 months prior to randomization. Additionally, patients needed to have an ECOG performance status of 0 or 1 and a tissue sample for biomarker assessment.

Eligible patients were randomly assigned in a 1:1 fashion to receive 200 mg of intravenous pembrolizumab once every 3 weeks for up to 35 cycles plus 160 mg of oral enzalutamide per day and ADT, or IV placebo once every 3 weeks for up to 35 cycles plus 160 mg of oral enzalutamide per day and ADT.

Patients were stratified by prior docetaxel treatment (yes vs no) and high-volume disease (yes vs no).

Key secondary end points included time to first subsequent therapy, time to first symptomatic skeletal-related event, and safety.

The median age of patients treated in the pembrolizumab arm was 68 years (range, 43-91), and 33.5% of those patients had an ECOG performance status of 1. Notably, 96.5% of patients had bone metastases, 20.3% had visceral metastases, and 62.6% had high-volume disease.

Furthermore, 23.6% of patients had a Gleason sum of 7 or less, 73.2% had a sum of 8 or more; 39.6% had measurable disease per RECIST v1.1 criteria; and 10.2% had prior docetaxel treatment for mHSPC. Regarding PD-L1 status, 38.0% were positive, 60.2% were negative, and 1.8% were unknown.

In the placebo group, the median age was 68 years (range, 37-90); 29.0% of patients had an ECOG performance status of 1; 97.4% of patients had bone metastases; 19.0% had visceral metastases; and 63.7% had high-volume disease.

Regarding Gleason sum, 19.8% of patients had a sum of 7 or less, and 77.9% had a sum of 8 or more. Additionally, 39.2% had measurable disease by RECIST v1.1 criteria; 9.8% had prior docetaxel treatment for mHSPC; 40.3% of patients were PD-L1 positive; 58.1% were PD-L1 negative; and 1.6% had an unknown PD-L1 status.

Subgroups analyses showed that rPFS and OS data were consistent across predefined subsets of patients.

Looking to safety, 98.9% of patients treated with the pembrolizumab combination experienced any-grade, any-cause adverse effects (AEs) vs 95.2% of patients treated with the placebo combination. The rates of grade 3 to 5 AEs were 61.9% and 38.1%, respectively. The rates of serious any-cause AEs were 40.3% and 23.2%, respectively. AEs led to treatment discontinuation in 33.4% of patients in the pembrolizumab arm and 8.2% of patients in the placebo arm. AEs led to death in 5.3% of patients in the pembrolizumab arm and 2.6% of patients in the placebo arm.

Notably, 43.2% of patients treated with the study combination experienced immune-mediated AEs and infusion reactions, 21.4% of which were grades 3 to 5. These rates were 7.5% and 1.3%, respectively, in patients treated with the placebo combination.

The most common any-grade AEs of any cause across both treatment groups were fatigue (31.2% vs 28.6% for pembrolizumab and placebo, respectively), arthralgia (29.1% vs 25.8%), rash (25.1% vs 9.3%), diarrhea (20.6% vs 11.8%), and hot flush (17.6% vs 23.0%).

“The role of immune checkpoint inhibition in prostate cancer remains unclear, and further studies are needed to identify patients most likely to benefit,” Gratzke concluded.

Reference

Gratzke C, Özgüroğlu M, Peer A, et al. Pembrolizumab plus enzalutamide and androgen deprivation therapy for patients with metastatic hormone-sensitive prostate cancer: randomized double-blind phase 3 KEYNOTE-991 study. Ann Oncol. 2023;34(suppl 2):S957-S958. doi.org/10.1016/j.annonc.2023.09.2722.