The phase III KEYNOTE-921 trial has found that adding pembrolizumab to docetaxel chemotherapy failed to significantly improve outcomes in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC), according to results published in the Journal of Clinical Oncology.
The global, double-blind study enrolled 1,030 patients who had experienced disease progression after androgen-deprivation therapy and one androgen receptor pathway inhibitor. Participants were randomized to receive docetaxel at 75 mg/m² every three weeks for up to 10 cycles with concomitant prednisone at 5 mg twice daily, plus either pembrolizumab at 200 mg (n=515) or matched placebo (n=515) every three weeks for up to 35 cycles.
Primary Endpoints Not Met
With a median follow-up of 22.7 months, the trial failed to meet its dual primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS).
At the first interim analysis, median rPFS was 8.6 months in the pembrolizumab/docetaxel group versus 8.3 months in the control group (hazard ratio [HR]=0.85, 95% CI=0.71-1.01, P=0.03). Since this difference did not reach the predefined significance level of P=0.02, no further testing for rPFS was performed.
At final analysis, median OS was 19.6 months in the pembrolizumab/docetaxel group compared to 19.0 months in the docetaxel-alone group (HR=0.92, 95% CI=0.78-1.09, P=0.17). The 12-month OS rates were 76.9% versus 73.2%, while 24-month rates were 39.4% versus 38.5%, respectively.
"The addition of pembrolizumab to docetaxel did not significantly improve efficacy outcomes for participants with previously treated mCRPC. The current standard of care remains unchanged," stated corresponding author Daniel P. Petrylak, MD, of Yale Cancer Center.
Potential Signal in PD-L1 Positive Subgroup
Interestingly, a subgroup analysis revealed a potential benefit in patients with PD-L1-positive disease. In this population, median OS was 19.8 months with the combination therapy versus 14.9 months with docetaxel alone (HR=0.71, 95% CI=0.51-0.98). However, no benefit was observed in PD-L1-negative patients (median OS: 19.6 vs 20.8 months; HR=0.99).
Similarly, in PD-L1-positive patients, median rPFS was 8.3 months with pembrolizumab/docetaxel versus 7.4 months with placebo/docetaxel (HR=0.71, 95% CI=0.50-1.00).
"This finding suggests that further investigation of immunotherapy in biomarker-selected prostate cancer populations may be warranted," noted lead study author Karim Fizazi, MD, PhD, a professor of Oncology at the University of Paris Saclay.
Secondary Endpoints and Response Rates
The trial also assessed several secondary endpoints. The median time to initiation of first subsequent anticancer therapy was 10.7 months with pembrolizumab plus docetaxel compared with 10.4 months with placebo plus docetaxel (HR=0.86, 95% CI=0.74-1.01).
Overall response rates were similar between the two arms: 33.5% (95% CI=27.0%-40.4%) with pembrolizumab/docetaxel versus 35.3% (95% CI=29.0%-42.0%) with placebo/docetaxel. The median duration of response was also comparable at 6.3 months versus 6.2 months, respectively.
Safety Profile
Treatment-related adverse events (TRAEs) occurred in 94.6% of patients who received pembrolizumab and 94.9% who received placebo. Grade ≥3 TRAEs were more common in the pembrolizumab group (43.2% vs 36.6%).
The most common TRAEs of any grade were alopecia, diarrhea, and fatigue. Immune-mediated adverse events were more frequent with pembrolizumab, with pneumonitis being the most common (7.0% vs 3.1%).
Treatment-related serious adverse events occurred in 20.2% of the pembrolizumab group versus 15.2% of the control group. Two treatment-related deaths occurred in the pembrolizumab/docetaxel group (from pneumonitis and interstitial lung disease) compared to seven in the control group (from various causes including sepsis, pneumonia, and respiratory failure).
Implications for Prostate Cancer Treatment
The KEYNOTE-921 results represent another setback in the quest to incorporate immunotherapy into prostate cancer treatment regimens. Despite the success of immune checkpoint inhibitors in various cancer types, prostate cancer has generally shown resistance to these approaches.
"New efficacious therapeutic options for metastatic castration-resistant prostate cancer remain an unmet need," emphasized Dr. Fizazi and colleagues in their publication.
The trial enrolled patients who were 18 years and older with histologically or cytologically confirmed adenocarcinoma of the prostate that had progressed on androgen deprivation therapy or after bilateral orchiectomy, with evidence of metastatic disease. All patients had adequate organ function, an ECOG performance status of 0 or 1, and ongoing androgen deprivation.
While the overall results were disappointing, the signal observed in PD-L1-positive patients suggests that a more targeted approach to patient selection might be necessary for future immunotherapy trials in prostate cancer.
