PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone for ARPI-pretreated and chemotherapy-naive metastatic castration-resistant prostate cancer: a pooled analysis of KEYNOTE-921 and CheckMate 7DX trials.

[BACKGROUND] The optimal treatment strategy for androgen receptor pathway inhibitor (ARPI)-pretreated and chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) remains unclear. Chemotherapy has limited efficacy as a monotherapy in unselected mCRPC patients. In contrast, the addition of PD-1/PD-L1 inhibitors to chemotherapy (Chemo-IO) may enhance antitumor activity. We conducted a meta-analysis using data from phase 3 randomized controlled trials (RCTs), with the objective of assessing the comparative efficacy and safety of Chemo-IO and chemotherapy alone in this population.

[METHODS] Six databases were searched. We included phase 3 RCTs that compared Chemo-IO with chemotherapy alone. The study defined radiographic progression-free survival (rPFS) and overall survival (OS) as the primary outcomes. Secondary outcome measures comprised the survival rates, objective response rate (ORR), and safety. Hazard ratios (HRs) and risk ratios (RRs) were pooled; the choice between fixed- and random-effects models depended on the observed heterogeneity.

[RESULTS] KEYNOTE-921 and CheckMate 7DX trials, involving 2060 patients, were ultimately included. There were no significant differences in rPFS (HR: 0.91 [0.81-1.03], P = 0.13) or OS (HR: 0.99 [0.87-1.12], P = 0.83) between the two groups. PD-L1-positive status correlated with superior survival outcomes (OS and rPFS) among patients treated with the Chemo-IO regimen. In addition, there were no significant differences in ORR (RR: 1.01 [0.80-1.27], P = 0.94), disease control rate (DCR; RR: 1.02 [0.90-1.15], P = 0.76), or PSA response (RR: 0.98 [0.89-1.09], P = 0.71) between the groups. The incidence of grade 3-5 treatment-related adverse events (TRAEs), TRAE-related dose delays, and discontinuations was higher among patients receiving Chemo-IO. Within this treatment arm, the most frequent grade 3-5 TRAEs were decreased neutrophil count (7.98%), neutropenia (7.20%), and anemia (3.98%). At the cutoff, more patients in the Chemo-IO group were excluded due to AEs, whereas fewer were excluded due to disease progression.

[CONCLUSIONS] Chemo-IO did not improve survival or response compared with chemotherapy alone in unselected ARPI-pretreated and chemotherapy-naïve mCRPC and was associated with increased toxicity, although a potential benefit was observed in PD-L1-positive patients.

[TRAIL REGISTRATION] PROSPERO ID: CRD 420261284437.