Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial

Abstract

Gerburg M. Wulf and Ursula A. Matulonis contributed equally to this work CONTRIBUTORS PAK contributed to study concept, design, oversight, data collection and interpretation and writing of the manuscript. WTB contributed to the study design, data analysis and interpretation, writing and creation of figures. MB, LCC, JFL, MKB contributed to patient recruitment and study design and conception. CA and RLC and SNW contributed to the study design, data interpretation, critically reviewed manuscript drafts. ROC contributed to patient data collection, data interpretation and critically reviewed manuscript drafts. CA and RLC contributed to patient data collection. SHK contributed to data interpretation and writing. JE contributed preclinical data and data interpretation. GC contributed data analysis, data interpretation, manuscript writing. JC contributed to data collection. PK contributed to study oversight, data collection and interpretation. BK contributed to preclinical and correlative work. SP contributed to preclinical work supporting this study. EW contributed to patient recruitment, study design and conception. SF contributed to collection and assembling of data. CW contributed to data collection and assembly. KC contributed to data interpretation, critically reviewed manuscript drafts, and contributed to patient data collection. ELM contributed to patient recruitment, study design and conception. WL contributed to study design, data analysis, data interpretation, reviewed manuscript drafts. GBM contributed to the development of the concepts and the initiation of the trial. EMS contributed to the study design, data collection, data analysis, data interpretation and critically reviewed manuscript drafts. ADD performed preclinical studies supporting this paper. GMW contributed to study design, data collection, analysis and interpretation, writing. UAM contributed to the initial study design, holds the FDA IND for this study, enrolled patients to this trial, contributed to data collection, data interpretations and analysis, reviewed manuscript drafts. All authors participated in writing the paper and approved the final version of the paper.

PARP and PARG inhibitors in cancer treatment

“…PARP inhibitors further synergize with inhibitors of the PI3K pathway, as shown in BRCA-proficient TNBC, BRCA1 mutated breast cancer mouse models, PIK3CA mutated ovarian cancer cells, and PTEN mutated endometrial cancer cells Juvekar et al 2012;Wang et al 2016b;Philip et al 2017). A phase I clinical trial revealed synergistic effects between olaparib and the PI3K inhibitor alpelisib in epithelial ovarian cancer, which are most likely based on HR suppression through reduced RAD51 protein levels and RAD51 foci formation (Konstantinopoulos et al 2019). The combination of talazoparib and the mTOR inhibitor everolimus synergistically kills BRCA-proficient TNBC by inducing HR deficiency through repression of the histone methyltransferase SUV39H1 (Mo et al 2016).…”

PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

“…between PARP inhibition and HR deficiency by simultaneous chemical inhibition of PARP and HR in cells genetically proficient for HR [22]. Such chemically induced synthetic lethal approaches open the possibility of treating many types of cancer that are either deficient or proficient for HR.…”

Infection risk with PI3K-AKT-mTOR pathway inhibitors and immune checkpoint inhibitors in patients with advanced solid tumours in phase I clinical trials

“…16 Alpelisib in combination with olaparib also induced a noteworthy preliminary clinical response in epithelial ovarian cancer. 17 In the future, treatment opportunities for PAMs may increase for the treatment of a variety of malignant tumours harbouring PAM pathway alterations. We suggest that intense infection control and prevention might be required in the treatment with PAMs, especially in the use of dual inhibitors.…”