Pembrolizumab/Docetaxel Doesn’t Improve OS/rPFS Outcomes in mCRPC

Pembrolizumab with docetaxel did not elicit efficacy improvements vs placebo with docetaxel in previously treated castration-resistant prostate cancer.

Adding pembrolizumab (Keytruda) to docetaxel did not show significant improvements to efficacy in patients with previously treated metastatic castration-resistant prostate cancer, according to results from the phase 2 KEYNOTE-921 trial (NCT03834506) published in the Journal of Clinical Oncology.

At the final analysis, with a median time from assignment to data cut-off of 22.7 months, the median overall survival (OS) was 19.6 months (95% CI, 18.2-20.9) with pembrolizumab plus docetaxel compared with 19.0 months (95% CI, 17.9-20.9) with placebo plus docetaxel (HR, 0.92; 95% CI, 0.78-1.09; P = .17). In patients with PD-L1–positive disease, the median OS was 19.8 months (95% CI, 16.2-22.0) vs 14.9 months (95% CI, 12.4-18.2), respectively (HR, 0.71; 95% CI, 0.51-0.98); in those with PD-L1–negative disease, the median OS was 19.6 months (95% CI, 18.0-21.2) vs 20.8 months (95% CI, 18.7-23.8), respectively (HR, 0.99; 95% CI, 0.81-1.21).

At the first interim analysis, the median radiographic progression-free survival (rPFS) was 8.6 months (95% CI, 8.3-10.2) vs 8.3 months (95% CI, 8.2-8.5), respectively (HR, 0.85; 95% CI, 0.71-1.01; P = .03). In those with PD-L1–positive disease, the median rPFS was 8.3 months (95% CI, 8.1-9.9) vs 7.4 months (95% CI, 6.2-8.3), respectively (HR, 0.71; 95% CI, 0.50-1.00); in those with PD-L1–negative disease, the median rPFS was 9.0 months (95% CI, 8.4-10.3) vs 8.3 months (95% CI, 8.3-8.5), respectively (HR, 0.85; 95% CI, 0.69-1.05). There were no significant differences for rPFS in prespecified subgroups; no further testing for rPFS was done after this analysis.

The median time to initiation of the first subsequent anticancer therapy (TFST) was 10.7 months (95% CI, 10.4-11.1) with pembrolizumab plus docetaxel compared with 10.4 months (95% CI, 9.7-11.1) with placebo plus docetaxel (HR, 0.86; 95% CI, 0.74-1.01).

“The phase 3 KEYNOTE-921 study did not meet the predefined criteria for the superiority of pembrolizumab plus docetaxel vs placebo plus docetaxel for the dual primary end points of rPFS and OS in participants with chemotherapy-naive [metastatic castration-resistant prostate cancer] with disease progression after or intolerance to [androgen receptor pathway inhibitor],” lead study author Karim Fizazi, MD, PhD, a full professor in Oncology at the University of Paris Saclay in Villejuif, France, and coauthors, wrote in the paper. “New efficacious therapeutic options for [metastatic castration-resistant prostate cancer] remain an unmet need.”

KEYNOTE-921 was a randomized, double-blind trial that enrolled a total of 1030 patients who were randomly assigned to receive either 200 mg of intravenous pembrolizumab once every 3 weeks for 35 cycles or less (n = 515) or matched placebo (n = 515), both with 75 mg/m2 of intravenous docetaxel once every 3 weeks for at most 10 cycles and 5 mg of oral prednisone twice daily concomitantly with docetaxel.

Eligible patients were 18 years and older with histologically or cytologically confirmed adenocarcinoma of the prostate that progressed on androgen deprivation therapy or after bilateral orchiectomy and had evidence of metastatic disease on bone scans or in soft tissues. Additionally, patients had adequate organ function, an ECOG performance status of 0 or 1, and ongoing androgen deprivation. Those with previous radium or radiopharmaceuticals were excluded from trial participation.

The trial’s primary end points were rPFS by blinded independent central review and OS. Secondary end points include overall response rate (ORR), time to PSA progression, TFST, duration of response, and safety.

The ORR was 33.5% (95% CI, 27.0%-40.4%) with pembrolizumab and docetaxel vs 35.3% (95% CI, 29.0%-42.0%) with placebo and docetaxel; the median duration of response was 6.3 months (range, 3.4+ to 21.2) vs 6.2 months (range, 2.0+ to 13.1), respectively.

Treatment-related adverse events (TRAEs) occurred in 94.6% of patients who received pembrolizumab and 94.9% who received placebo; of grade 3 or higher, they occurred in 43.2% and 36.6%, respectively. Of any grade, the most common TRAEs were alopecia (34.6% vs 36.6%), diarrhea (34.6% vs 30.7%), and fatigue (30.9% vs 30.9%). There were 2 treatment-related deaths in the pembrolizumab group, 1 due to pneumonitis and 1 due to interstitial lung disease, and there were 7 treatment-related deaths in the placebo group, 1 each due to urosepsis, respiratory failure, pneumonia, neck abscess, febrile neutropenia, clostridial sepsis, and influenzal pneumonia.

Reference

Petrylak DP, Ratta R, Matsubara N, et al. Pembrolizumab plus docetaxel versus docetaxel for previously treated metastatic castration-resistant prostate cancer: the randomized, double-blind, phase III KEYNOTE-921 Trial. J Clin Oncol. Published online March 05, 2025. doi:10.1200/JCO-24-01283