(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 1st line setting). PARP inhibitors have previously demonstrated overall survival benefits in the 2nd 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 5th – April 8th, 2024
References:
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020 May 28;382(22):2091-2102.
- Abida W, Patnaik A, Campbell D, et al. Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol 2020 Nov 10;38(32):3763-3772.
- Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Engl J Med. 2023 Feb 23;388(8):719-732.
- Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomized, double-blind, phase 3 trial. Lancet Oncol. 2023 Oct;24(10):1094-1108.
- Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023 Jun 20;41(18):3339-3351.
- Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): A randomized, placebo-controlled, phase 3 trial. Lancet. 2023 Jul 22;402(10398):291-303.