High frequency of radiological differential responses with poly(ADP-Ribose) polymerase (PARP) inhibitor therapy

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Poly(ADP-Ribose) polymerase (PARP) inhibitors show clinical activity in cancers with germline BRCA1 and BRCA2 (BRCA1/2) mutations.
• However, patient responses to PARP inhibitors are variable, necessitating further investigation into predictive factors.
• Intrapatient radiological differential responses (RDR) represent a complex pattern of tumor behavior under treatment.

Purpose of the Study:

• To determine the rate of intrapatient radiological differential responses (RDR) to PARP inhibitors in advanced cancers.
• To assess the correlation between RDR and patient outcomes, including time to progression (TTP) and overall survival (OS).
• To identify factors associated with the development of RDR during PARP inhibitor monotherapy.

Main Methods:

• Retrospective review of 113 patients with advanced cancers from five early-phase PARP inhibitor monotherapy trials.
• Analysis of radiological scans to identify patterns of RDR (early vs. late).
• Correlation of RDR with patient outcomes (TTP, OS) and germline BRCA1/2 mutation status.

Main Results:

• 40.7% of patients developed RDR to PARP inhibitor monotherapy, with 69.6% of these being early responses.
• Early RDR was associated with significantly shorter TTP and OS compared to no RDR.
• Germline BRCA1/2 mutations were independently predictive of RDR (2.93-fold increased risk), with BRCA1 mutations correlating with worse outcomes than BRCA2 mutations.

Conclusions:

• Radiological differential responses to PARP inhibitors are frequent, particularly in patients with germline BRCA1/2 mutations.
• The occurrence of RDR, especially early RDR, is associated with poorer treatment outcomes.
• These findings suggest that intrapatient genomic heterogeneity may underlie variable responses and outcomes to PARP inhibitors.