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

// Raquel Perez-Lopez 1, 2, * , Desam Roda 1, 2, * , Begona Jimenez 2, * , Jessica Brown 2 , Joaquin Mateo 1, 2 , Suzanne Carreira 1 , Juanita Lopez 2 , Udai Banerji 1, 2 , L. Rhoda Molife 1, 2 , Dow-Mu Koh 2 , Stan B. Kaye 1, 2 , Johann S. de Bono 1, 2 , Nina Tunariu 1, 2, ** and Timothy A. Yap 1, 2, ** 1 The Institute of Cancer Research, London, United Kingdom 2 Royal Marsden NHS Foundation Trust, London, United Kingdom * These authors share co-first authorship ** These authors share co-senior authorship Correspondence to: Timothy A. Yap, email: tyap@mdanderson.org Keywords: PARP inhibitors; BRCA1 and BRCA2 mutations; radiological differential responses Received: June 26, 2017     Accepted: September 30, 2017     Published: November 06, 2017 ABSTRACT Despite impressive clinical activity in patients with germline BRCA1 and BRCA2 (BRCA1/2) mutant cancers, antitumor responses to poly(ADP-Ribose) polymerase (PARP) inhibitors are variable. We set out to assess the rate of intrapatient radiological differential responses (RDR) to PARP inhibitors, its correlation with patient outcomes, and the identification of factors associated with RDR. We retrospectively reviewed all patients with advanced cancers from five early phase PARP inhibitor monotherapy trials. 113 patients (ovarian cancers 57.5%; breast cancers 23.9%) were included in this retrospective study; 46 (40.7%) patients developed RDR on PARP inhibitor monotherapy. We identified two patterns of RDR: early RDR (1st or 2nd on-treatment scans) in 69.6% of patients, and late RDR (penultimate or final scans) in 30.4% of patients. Early RDR was associated with shorter time to progression (TTP) (225 vs 367 days, HR:0.59, 95%CI 0.36-0.98; p=0.04) and overall survival (OS) (499 vs 857 days; HR:0.47, 95%CI 0.27-0.82, p=0.006). Seventy-nine (69.9%) patients had known germline BRCA1/2 mutations; 49.4% of these BRCA1/2 mutation carriers developed RDR versus 20.6% of patients with unknown or wildtype BRCA1/2 status. Harboring germline BRCA1/2 mutations was independently predictive for RDR (RR:2.93, 95% CI 1.08-7.90, p=0.03). Patients with germline BRCA1 mutations had worse TTP and OS than BRCA2 mutation carriers (212 vs 406 days, HR:0.58, 95% CI 0.36-0.94, p=0.023 and 515 vs 937 days; HR:0.49, 95% CI 0.29-0.83; p=0.007). RDR with PARP inhibitors are frequent, particularly in germline BRCA1/2 mutation carriers. These findings have clinical implications for patient outcomes and may reflect underlying intrapatient genomic heterogeneity.