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

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.

SUBMITTER: Perez-Lopez R

PROVIDER: S-EPMC5732817 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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

Perez-Lopez Raquel R Roda Desam D Jimenez Begona B Brown Jessica J Mateo Joaquin J Carreira Suzanne S Lopez Juanita J Banerji Udai U Molife L Rhoda LR Koh Dow-Mu DM Kaye Stan B SB de Bono Johann S JS Tunariu Nina N Yap Timothy A TA

Oncotarget 20171106 61

Despite impressive clinical activity in patients with germline <i>BRCA1</i> and <i>BRCA2 (BRCA1/2)</i> 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 inhibi ...[more]

PMID: 29262651

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Project description:BackgroundOvarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide. Three-quarters of women present when the disease has spread throughout the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy.PARP (poly (ADP-ribose) polymerase) inhibitors, are a novel type of medication that works by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents. It is not clear how PARP inhibitors compare to conventional chemotherapy regimens for the treatment of ovarian cancer, with respect to survival, side effects and quality of life.ObjectivesTo determine the benefits and risks of PARP inhibitors for the treatment of epithelial ovarian cancer (EOC).Search methodsWe identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), the Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to May 2014), EMBASE (1990 to May 2014), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature.Selection criteriaWomen with histologically proven EOC who were randomised to treatment groups in trials that either compared PARP inhibitors with no treatment, or PARP inhibitors versus conventional chemotherapy, or PARP inhibitors together with conventional chemotherapy versus conventional chemotherapy alone.Data collection and analysisWe used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data, where possible. Outcomes included survival, quality of life and toxicity.Main resultsWe included four RCTs involving 599 women with EOC. Data for veliparib were limited and of low quality, due to small numbers (75 women total). Olaparib, on average, improved progression-free survival (PFS) when added to conventional treatment and when used as maintenance treatment in women with platinum-sensitive disease compared with placebo (hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.29 to 0.60; 426 participants ; two studies), but did not improve overall survival (OS) (HR 1.05, 95% CI 0.79 to 1.39; 426 participants; two studies). We graded this evidence as moderate quality using the GRADE approach. Olaparib was associated with more severe adverse events (G3/4) during the maintenance phase compared with controls (risk ratio (RR) 1.74, 95% CI 1.22 to 2.49; 385 participants, two studies; moderate quality evidence). Quality of life data were insufficient for meta-analysis. We identified four ongoing studies.Authors' conclusionsPARP inhibitors appear to improve PFS in women with recurrent platinum-sensitive disease. Ongoing studies are likely to provide more information about whether the improvement in PFS leads to any change in OS in this subgroup of women with EOC. More research is needed to determine whether PARP inhibitors have any role to play in platinum-resistant disease.

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

Publications

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

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