Olaparib and ceralasertib (AZD6738) in patients with triple-negative advanced breast cancer: Results from Cohort E of the plasmaMATCH trial (CRUK/15/010)

Purpose: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC. Patients and Methods: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1–7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response. Results: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4–25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci. Conclusions: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy

Normal aging and decision making: The role of motivation

The main argument of this review is that motivational development associated with normal aging affects decision making. With increasing age, the ratio of gains to losses becomes more and more unfavorable. Reflecting the increasing losses in resources, goal orientation changes from a predominant orientation towards gains in young adulthood to an increasingly stronger orientation towards the prevention of loss in older adulthood. As goals serve as reference points for the evaluation of decision outcomes, this change in goal orientation across adulthood might also affect decision making. The decision-making literature has recognized that choices are influenced by goal orientation. However, little research has been conducted on how goals influence the decision-making process in general and with regard to aging in particular. To date, findings on decision making and aging remain inconsistent and are in need of a developmental framework. With regard to applications, a better understanding of the aging decision maker can provide insight into how to improve communication efforts about issues like advance care planning, medical treatment, and housing options