Resistance to Poly (ADP-Ribose) Polymerase Inhibitors (PARPi): Mechanisms and Potential to Reverse.

PURPOSE OF REVIEW: This review will focus on the most common mechanisms for poly (ADP-ribose) polymerase inhibitors' (PARPi) resistance and the main strategies for overcoming acquired or de novo PARPi resistance. RECENT FINDINGS: Initial approvals for PARPi as part of treatment for advanced epithelial ovarian cancer (EOC) started in 2014 with patient with recurrent cancer characterized by BRCA mutations in the 3rd and 4th line and now have approvals for front-line maintenance in both the BRCA mutated and BRCAwt populations. As with all therapies, patients will eventually develop resistance to treatment. The most common mechanisms for PARPi resistance include reversion mutations, methylation events, and restoration of homologous recombination deficiency (HRD) through combinations and targeting replication stress. As more and more patients receive initial treatment (and potential retreatment with PARPi), we need to better understand the mechanisms in which tumors acquire PARPi resistance.

PARP inhibitors in the treatment of ovarian cancer: a review.

PURPOSE OF REVIEW: This article will review recent changes in the standard of care for olaparib, niraparib, and rucaparib, as well as ongoing trials evaluating this class of drugs in combination with antiangiogenic agents and PD-1/PD-L1 inhibitors. RECENT FINDINGS: Niraparib received FDA approval for use in patients with complete response or partial response to first-line platinum-based chemotherapy regardless of BRCAm or HRD status that was received in April 2020. FDA approval was received for olaparib in combination with bevacizamab for epithelial ovarian cancer patients with complete response/partial response to first-line chemotherapy and bevacizumab and g/sBRCA and/or genomic instability by Myriad myChoice CDx in May 2020. SUMMARY: In the last year, treatment with PARPi has extended to not only include BRCAm and HRD-deficient patients but also have shown improvement in outcomes in HRD-proficient patients. With these advancements, more patients can access these agents and receive benefit. In the upcoming years, it will be exciting to see the potential benefit when PARPs are added to other angiogenic antagonists and immunotherapy agents.

Knowledge of endometrial cancer risk factors in a general gynecologic population.

OBJECTIVES: To determine knowledge regarding endometrial cancer (EC) risk factors in a general gynecologic patient population. STUDY DESIGN: A questionnaire survey regarding health behaviors and knowledge of risk factors of EC was administered to patients presenting for routine gynecologic care at two general gynecologic practices affiliated with a tertiary-care center between August and October 2014. Patient demographics, lifestyle information, and knowledge regarding EC risk factors were assessed. Data were analyzed using univariable and bivariable analyses, Χ2 tests, Fischer's exact tests, and t-tests. RESULTS: 231 women responded. Median age was 56 years old (IQR 25-64), and 87% were Caucasian. Median BMI was 24.9 (IQR 22.3-29.2). 24.7% were overweight and 24.3% obese. The majority (69.4%) of patients received a college or graduate degree. Over half of the women (52.1%) did not know that obesity was associated with increased risk of EC. When dichotomized based on obese vs non obese, there was no difference in patients' knowledge of the association between obesity and EC (47% vs 48%, respectively, p = .93). 91% of all respondents reported that their gynecologist or primary care physician had never discussed the risks of EC with them. CONCLUSIONS: Regardless of education level, age or obesity status, the majority of women did not know the common risks of EC. Increased efforts towards educating women regarding obesity and other risk factors of EC are necessary in order to reduce the rising incidence of EC, a predominantly obesity-driven disease. Interventions must include general obstetrician-gynecologists and primary care providers.

Olaparib in the treatment of ovarian cancer.

The poly ADP ribose polymerase olaparib is currently approved in front line BRCA-associated epithelial ovarian cancer (EOC), platinum-sensitive recurrence agnostic to BRCA status and for gBRCA as treatment in the fourth line and beyond. Women who are diagnosed with advanced stage EOC face a formidable challenge in overcoming their disease and achieving long-term, disease-free survival. The qualifier here is disease free. EOC is largely exquisitely chemosensitive, especially in the treatment naive (first line) setting and the expectation is that the vast majority of women will complete front line platinum-based chemotherapy with a response. When unselected (not selected by BRCA) women are enrolled on clinical trials, the response rate among those who have measurable disease at the time of chemotherapy initiation is 48% for carboplatin/paclitaxel and 67% for carboplatin/paclitaxel plus bevacizumab. When one considers the addition of women who start chemotherapy without measurable disease, they will likely also end chemotherapy without measurable disease and the overall rate of no evidence of disease at conclusion of chemotherapy approaches 80%. Despite this, the majority of women will suffer relapse of their disease, typically within the first 3 years following completion of therapy. Once recurrent, the disease is highly treatable for many years but no longer considered curable. This review will cover indications for olaparib in ovarian cancer as well as ongoing combination trials and rationale for these combinations.