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Published on: November 19, 2019
The Impact of Uncommon HRR Alterations as Predictors of Efficacy of PARP Inhibitors in Metastatic
Giada Pinterpe1, Fortuna Migliaccio2, Chiara Ciccarese3
1Clinica Oncologica e Centro Regionale di Genetica Oncologica, AOU delle Marche, Ancona, Italy.
Background:
Metastatic castration-resistant prostate cancer (mCRPC) patients with BRCA1/2 mutations show significant responses to poly-ADP ribose polymerase inhibitors (PARPi), while the efficacy of these agents in patients with homologous recombination repair (HRR) gene alterations other than BRCA remains unclear.
Objective:
This meta-analysis aimed at assessing the efficacy of PARPi in mCRPC harboring alterations in four rare HRR genes (i.e. CDK12, PALB2, ATM, and CHEK2).
Patients And Methods:
Five randomised phase III trials (PROfound, PROpel, MAGNITUDE, TALAPRO-2, TRITON3) were selected through searching the Medline/PubMed, Cochrane Library, and ASCO Meeting abstracts. Data extraction followed the PRISMA statement. The primary endpoints, radiographic progression-free survival (rPFS) and overall survival (OS) with the relative 95% CI, were calculated using fixed- or random-effects methods, depending on the studies' heterogeneity. RevMan software for meta-analysis (v.5.2.3) was used.
Results:
PARPi significantly improved rPFS in mCRPC patients with CDK12 alterations (hazard ratio (HR) = 0.65; p = 0.02) without OS benefit. In patients with ATM, CHEK2, or PALB2 alterations, no significant benefit was observed in rPFS or OS. Due to the low incidence of these rare mutations, we grouped them into gene panels, revealing a significant rPFS advantage when CDK12+PALB2 (HR = 0.63; p = 0.009) were combined, and a similar benefit when including CHEK2 in the gene panel (HR = 0.69; p = 0.01).
Conclusion:
CDK12 alterations could be considered as a predictive biomarker of rPFS benefit with PARPi. A gene panel grouping CDK12 and PALB2 with or without CHEK2 mutations could also enable prediction of rPFS benefit with PARPi.
Insights
Poly-ADP ribose polymerase inhibitors (PARPi) show significant radiographic progression-free survival (rPFS) benefits in metastatic castration-resistant prostate cancer (mCRPC) patients with CDK12 alterations. A gene panel including CDK12 and PALB2, with or without CHEK2 mutations, may also predict PARPi efficacy.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) patients with BRCA1/2 mutations respond well to poly-ADP ribose polymerase inhibitors (PARPi).
- The effectiveness of PARPi in mCRPC patients with other homologous recombination repair (HRR) gene alterations is not well understood.
- This study focuses on rare HRR gene alterations beyond BRCA.
Purpose of the Study:
- To evaluate the efficacy of PARPi in mCRPC patients with alterations in CDK12, PALB2, ATM, and CHEK2.
- To identify potential predictive biomarkers for PARPi treatment in mCRPC.
Main Methods:
- A meta-analysis of five randomized phase III trials (PROfound, PROpel, MAGNITUDE, TALAPRO-2, TRITON3).
- Data extraction followed PRISMA guidelines, focusing on radiographic progression-free survival (rPFS) and overall survival (OS).
- RevMan software was used for meta-analysis calculations.
Main Results:
- PARPi significantly improved rPFS in mCRPC patients with CDK12 alterations (HR = 0.65; p = 0.02), but no OS benefit was observed.
- No significant rPFS or OS benefit was found for ATM, CHEK2, or PALB2 alterations individually.
- Combining CDK12 and PALB2 (HR = 0.63; p = 0.009), or including CHEK2 (HR = 0.69; p = 0.01), showed a significant rPFS advantage.
Conclusions:
- CDK12 alterations are a potential predictive biomarker for PARPi efficacy in terms of rPFS.
- A gene panel combining CDK12 and PALB2, with or without CHEK2 mutations, may predict rPFS benefit from PARPi treatment.
- Further research may refine patient selection for PARPi therapy based on specific HRR gene profiles.
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