To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among metastatic castrate-resistant prostate cancer (mCRPC) patients receiving combination first-line poly(ADP-ribose) polymerase inhibitors (PARPi) plus androgen receptor axis-targeted agents (ARATs) versus placebo/ARAT.
We conducted a systematic review/meta-analysis of all published phase III randomized controlled trials using EMBASE, MEDLINE, and Cochrane (inception until June 6, 2023). Published full-text manuscripts and conference abstracts were inclusion eligible. Study selection/data extraction were independently performed by two authors. The Cochrane Risk-of-Bias 2 Tool was used, and certainty of evidence assessed using the GRADE framework. Pooled hazard ratios and relative risks, with corresponding confidence intervals, were generated using random effects models.
Three trials were identified: PROpel, MAGNITUDE, and TALAPRO-2. Compared to placebo/ARATs, PARPi/ARAT combination was associated with a 35% rPFS improvement in the overall cohort (HR: 0.65, 95% CI: 0.56-0.76), with 68%, 45%, and 26% improvements in the BRCA1/2-mutated (p<0.001), HRRm (p<0.001), and non-HRRm cohorts (p=0.003), respectively. OS data maturity ranged from 31-48%, with overall cohort OS data unavailable from MAGNITUDE. PROpel/TALAPRO-2 pooled analysis demonstrated a 16% OS improvement in the overall cohort (HR: 0.84, 95 CI: 0.72-0.98, p=0.02). OS in the HRRm (HR: 0.76, 95% CI: 0.61-0.95) and the BRCA1/2-mutated cohorts (HR: 0.53, 95% CI: 0.18-1.56) were improved, with a higher effect magnitude compared to the overall cohort. This combination was associated with a 45% relative risk increase in grade≥3 TEAEs, including 6.22-fold for grade≥3 anemia (31.9% versus 4.9%).
PARPi addition to ARATs in the first-line mCRPC setting is associated with rPFS benefits across subgroups, with the greatest magnitude of benefit in BRCA1/2-mutated patients. OS benefits remain inconsistent irrespective of HRRm status, with significant increases in grade≥3 TEAEs, particularly anemia. Currently, we suggest this combination approach be selectively offered to HRRm patients, preferentially BRCA1/2-mutated.
BJU international. 2023 Jul 17 [Epub ahead of print]
Rashid K Sayyid, Zachary Klaassen, Alejandro Berlin, Soumyajit Roy, Leonardo R Brandão, Rui Bernardino, Julian Chavarriaga, Di Maria Jiang, Daniel E Spratt, Neil E Fleshner, Christopher J D Wallis
Division of Urologic Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Section of Urology, Department of Surgery, Augusta University, Augusta, GA., Department of Radiation Oncology, University of Toronto; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON., Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA., Department of Pediatrics, Sick Kids Hospital, Toronto, ON, Canada., Division of Medical Oncology, Department of Medicine, Princess Margaret Cancer Centre, Toronto, ON., Department of Radiation Oncology, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.