EAU 2024: PARP Inhibitor Plus Androgen Receptor Pathway Inhibitor Combinations for 1st Line mCRPC: A Systematic Review and Meta-Analysis

(UroToday.com) The 2024 European Association of Urology (EAU) annual meeting featured a session on metastatic prostate cancer, and a presentation by Dr. Rashid Sayyid discussing a systematic review and meta-analysis of PARP inhibitors + androgen receptor pathway inhibitor combinations for first-line metastatic castrate-resistant prostate cancer (mCRCP). mCRPC patients have a median overall survival of 2-3 years with current 1st line agents, with outcomes specifically poor for BRCA1/2-mutated patients (comprising 8-11% of mCRPC patients in the 1^st line setting). PARP inhibitors have previously demonstrated overall survival benefits in the 2^nd line setting for HRR mutation mCRPC patients progressing on prior androgen receptor pathway inhibitors in the PROfound,¹ TRITON2² and TRITON3³ trials. Additionally, studies suggest that PARP inhibitors and androgen pathway receptor inhibitors may have synergistic mechanisms of action and improve clinical outcomes. Three phase 3 trials of combination PARP inhibitor + androgen pathway receptor inhibitor have been recently published (2022-2023) and included in this analysis:

PROpel: Olaparib + abiraterone⁴
MAGNITUDE: Niraparib + abiraterone⁵
TALAPRO-2: Talazoparib + enzalutamide⁶

The objective of this study presented at EAU 2024 was to compare radiographic progression-free survival, overall survival, and treatment-emergent adverse events among mCRPC patients receiving combination 1st line PARP inhibitor plus an androgen pathway receptor inhibitor versus placebo/androgen pathway receptor inhibitor.

Dr. Sayyid and colleagues conducted a systematic review/meta-analysis (PROSPERO CRD42023401122) of all published phase III trials comparing PARP inhibitor/androgen pathway receptor inhibitor combinations to placebo/androgen pathway receptor inhibitor in the 1st line mCRPC setting, using EMBASE, MEDLINE, and Cochrane (inception until March 23, 2023). Published full-text manuscripts and conference abstracts were inclusion eligible. Study selection/data extraction was independently performed by two authors, with disagreements resolved in consensus with a third author. The Cochrane Risk-of-Bias 2 Tool was used, and certainty of evidence was assessed using GRADE. Pooled estimates and 95% CIs were generated using random effects. Analysis was performed per initial study randomization and summary estimates from intention-to-treat analyses were included.

Compared to placebo/androgen pathway receptor inhibitor, PARP inhibitor/androgen pathway receptor inhibitor combination was associated with a 35% radiographic progression-free survival 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), HRR mutation (p<0.001), and non-HRR mutation cohorts (p=0.003), respectively:

Overall survival data maturity ranged from 31-48%, with overall cohort overall survival data unavailable from MAGNITUDE. PROpel/TALAPRO-2 pooled analysis demonstrated a 16% overall survival improvement in the overall cohort (HR: 0.84, 95 CI: 0.72-0.98):

Overall survival in the HRR mutation (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 treatment-emergent adverse events, including 6.22-fold for grade ≥3 anemia (31.9% versus 4.9%):

Limitations of this analysis include the significance between study heterogeneity, aggregated summary measures used instead of individual patient data, and GRADE certainty of evidence.

Dr. Sayyid concluded his presentation by discussing a systematic review and meta-analysis of PARP inhibitors + androgen receptor pathway inhibitor combinations for first-line mCRCP with the following statements:

1st line PARP inhibitors addition to androgen pathway receptor inhibitors for mCRPC is associated with radiographic progression-free survival benefits across patient subgroups, including non-HRR mutation, with the greatest benefit observed in BRCA1/2 mutation patients
Significant overall survival benefits were observed in the overall and HRR mutation cohorts, with the highest certainty of benefit in the BRCA1/2 mutation cohort
The PARP inhibitor/androgen pathway receptor inhibitor combination is associated with a 6 fold increase in grade ≥3 anemia
The investigators suggest this combination be selectively offered to HRR mutation patients, preferentially BRCA1/2 mutated, until further overall survival data and methods to better identify patients most likely to benefit from this combination approach become available

Presented by: Rashid K. Sayyid, MD, MSc, University of Toronto, Toronto, Ontario, Canada

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 European Association of Urology (EAU) annual congress, Paris, France, April 5^th – April 8^th, 2024

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