ABSTRACT
Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP?ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA?associated cancers, especially high?grade OC and breast cancers. They lead to synthetic lethality in BRCA?mutated cells by stalling the replication forks in homologous recombination?deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA?associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance
ABSTRACT
Background: A Phase IV, single?arm study was conducted to assess the safety of osimertinib in Indian patients with epidermal growth factor receptor (EGFR) T790M mutation?positive stage IV non?small cell lung cancer (NSCLC). Methods: Enrolled patients received 80 mg osimertinib for six cycles or until disease progression or unacceptable toxicity or withdrawal. Primary safety variables included treatment?emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to discontinuation/interruption/change (D/I/C) of drug dose, and AEs of special interest (AESIs). AEs were summarized by the percentage of patients experiencing at least one occurrence of each event. Results: Of the 60 enrolled patients (median age 58 [range: 34�] years; 51.7% women) at eight sites, nine patients were discontinued prematurely due to disease progression (n = 7) and death (n = 2); median (range) duration of treatment was 126 (1�4) days. Median age of patients was 58 (34�) years; 51.7% (n = 31) were women; 86.7% (n = 52) were nonsmokers; and most of them (98.3%) had adenocarcinoma. About 75% (n = 45) of patients experienced any of the TEAEs, with the most frequent being fatigue and creatine phosphokinase (CPK) increase (n = 6, 10% each). TEAEs in 11 (18.3%) patients were judged as study treatment related, with CPK increase being the most common (n = 4, 6.7%). TEAEs led to D/I/C of drug dose in eight (13.3%) patients, with one being study treatment related. Nine (15%) patients had AESIs of dyspnea (n = 6), chest pain (n = 2), and cardiorespiratory arrest (n = 1); two of them had a fatal outcome. One AESI (mild dyspnea) was considered study drug related. TEAEs of grade ?3 were reported in seven (11.7%) patients, including dyspnea in two (3.3%), followed by diarrhea, mucosal inflammation, cardiorespiratory arrest, and others (n = 1,1.7% each). None of the SAEs and fatal events were considered as study treatment related. Seven (11.7%) patients had abnormal electrocardiogram (ECG; not clinically significant) at the end of the study. Conclusion: Our study confirms the favorable safety profile of osimertinib without any new safety concerns in Indian patients with EGFR T790M mutation?positive stage IV NSCLC. ClinicalTrials.gov Identifier: NCT03853551 CTRI registration no. CTRI/2018/10/015941