Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations)

Abstract

PURPOSE Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapy in cancers with homologous recombination repair deficiency. However, efficacy is limited by both intrinsic and acquired resistance. The Olaparib Combinations basket trial explored olaparib alone and in combination with other homologous recombination–directed targeted therapies. Here, we report the results of the arm in which olaparib was combined with the orally bioavailable ataxia telangiectasia and RAD3-related inhibitor ceralasertib in patients with relapsed or refractory cancers harboring DNA damage response and repair alterations, including patients with BRCA-mutated PARP inhibitor–resistant high-grade serous ovarian cancer (HGSOC). PATIENTS AND METHODS Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Olaparib was administered at 300 mg twice daily and ceralasertib at 160 mg daily on days 1-7 in 28-day cycles until progression or unacceptable toxicities. Primary end points were confirmed complete response (CR) or partial response (PR) rates and clinical benefit rate (CBR; CR + PR + stable disease [SD] at 16 weeks). RESULTS Twenty-five patients were enrolled, with median four prior therapies. Five patients required dose reductions for myelosuppression. Overall response rate was 8.3% and CBR was 62.5% among the entire cohort. Two of five patients with tumor harboring ATM mutation achieved CR or SD ongoing at 24+ months, respectively (CBR 40%). Of seven patients with PARP inhibitor–resistant HGSOC, one achieved PR (–90%) and five had SD ranging 16-72 weeks (CBR 86%). CONCLUSION Olaparib with ceralasertib demonstrated preliminary activity in ATM-mutated tumors and in PARP inhibitor–resistant BRCA1/2–mutated HGSOC. These data warrant additional studies to further confirm activity in these settings.

Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and Deficient Murine Ovarian Cells

“…DDR inhibitors are reported to be very active in combination treatments, in vitro and in vivo ovarian cancer models [ 43 ], and in some cases can overcome PARPi resistance (for a recent review see [ 44 , 45 ]). Indeed, early clinical trials of PARPi combined with Wee1, Chk1 and ATR inhibitors have been explored in different subsets of OC patients [ 46 , 47 , 48 , 49 , 50 ]. We tested the combination of Wee1, Chk1 and ATR inhibitors with olaparib in our models ( Figure 5 and Figure S6 ).…”

PARP Inhibitors Resistance: Mechanisms and Perspectives

“…A phase I trial combining the AKT inhibitor capivasertib with olaparib revealed durable responses in patients with advanced-stage solid tumors, irrespective of BRCA1/2 status [59]. Another study showed a potential clinical activity with manageable toxicity with ceralasertib, an AKT inhibitor, in combination with olaparib in BRCA-mutated PARPi-resistant HGSOC, with a duration of benefit that exceeded the duration achieved on prior PARPi monotherapy [60,61].…”

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

“…Even though these drugs display similar toxicities, preliminary data suggest that they can be combined safely, adopting dose and schedule adjustments [ 130 ]. The association of olaparib and ceralasertib seems to be better tolerated compared to olaparib and prexasertib, especially in terms of hematological toxicities [ 131 , 132 , 133 ]. However, additional studies are necessary, even in this case, to clarify the safety profile of these combinations.…”