To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving a combination of first-line poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) plus androgen receptor axis-targeted agents (ARAT) vs placebo/ARAT.
Materials and Methods:
We conducted a systematic review/meta-analysis of all published Phase III randomised controlled trials using EMBASE, MEDLINE, and Cochrane (inception until 6 June 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 Grading of Recommendations, Assessment, Development, and Evaluations framework. Pooled hazard ratios (HRs) and relative risks, with corresponding confidence intervals (CIs), were generated using random-effects models.
Results:
Three trials were identified: PROpel, MAGNITUDE, and TALAPRO-2. Compared to placebo/ARAT, the 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 BReast CAncer gene 1/gene 2 (BRCA1/2)-mutated (BRCA1/2m; P < 0.001), homologous recombination repair-mutated (HRRm; P < 0.001), and non-HRRm cohorts (P = 0.003), respectively. OS data maturity ranged from 31% to 48%, with overall cohort OS data unavailable from MAGNITUDE. The 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 BRCA1/2m 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 anaemia (31.9% vs 4.9%).
Conclusions:
The addition of PARPi to ARAT in the first-line mCRPC setting is associated with rPFS benefits across subgroups, with the greatest magnitude of benefit in BRCA1/2m patients. OS benefits remain inconsistent irrespective of HRRm status, with significant increases in Grade ≥3 TEAEs, particularly anaemia. Currently, we suggest this combined approach be selectively offered to HRRm patients, preferentially BRCA1/2m.
Rashid K Sayyid 1, Zachary Klaassen 2, Alejandro Berlin 3 4, Soumyajit Roy 5, Leonardo R Brandão 6, Rui Bernardino 1, Julian Chavarriaga 1, Di Maria Jiang 7, Daniel E Spratt 8, Neil E Fleshner 1, Christopher J D Wallis 1 9
- Division of Urologic Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Section of Urology, Department of Surgery, Augusta University, Augusta, GA, USA.
- Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.
- 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, Canada.
- Department of Radiation Oncology, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.
- Department of Surgery, Urology, Mount Sinai Health System, Toronto, ON, Canada.