Neutropenia events with androgen receptor pathway inhibitor-containing versus control therapies in prostate cancer patients: a systematic review and meta-analysis

To systematically evaluate the risk of neutropenia associated with androgen receptor pathway inhibitor (ARPI) intensification in patients with prostate cancer across phase 3 randomized controlled trials. This systematic review and meta-analysis was conducted in accordance with PRISMA guidance. PubMed, Web of Science, the Cochrane Library, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform were searched for phase 3 randomized controlled trials evaluating ARPI-containing regimens in prostate cancer. The primary outcomes were any grade and grade 3 or higher neutropenia. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Exploratory subgroup and sensitivity analyses were performed, and certainty of evidence was assessed using the GRADE framework. Eight phase 3 randomized controlled trials were included. Seven trials involving 8,921 patients contributed to the analysis of any grade neutropenia, with 172 events among 4,897 patients in the ARPI-intensification arms and 118 among 4,024 patients in matched control arms (3.5% vs 2.9%). ARPI intensification was associated with a modest increase in any grade neutropenia (RR, 1.35; 95% CI, 1.07–1.69; p = 0.010), with minimal heterogeneity ( I 2 = 1.8%). Six trials involving 7,668 patients contributed to the analysis of grade 3 or higher neutropenia, with 302 events among 4,046 patients in the ARPI-intensification arms and 284 among 3,622 patients in control arms (7.5% vs 7.8%). No statistically significant increase was observed for grade 3 or higher neutropenia (RR, 1.09; 95% CI, 0.87–1.38; p = 0.453; I 2 = 0.0%). Exploratory analyses stratified by docetaxel use showed no significant between-subgroup differences, and sensitivity analyses were generally consistent with the primary findings. The certainty of evidence was moderate for any grade neutropenia and low for grade 3 or higher neutropenia. ARPI intensification compared with matched control regimens was associated with a modest increase in any grade neutropenia, whereas no significant increase was observed for grade 3 or higher neutropenia. Current randomized evidence does not establish that ARPIs independently increase the risk of severe neutropenia. Complete blood count monitoring may be individualized according to baseline hematologic risk and concomitant myelosuppressive therapy, particularly in patients receiving chemotherapy. Subgroup findings should be interpreted as exploratory.