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Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer

Open AccessPublished:October 04, 2021DOI:https://doi.org/10.1016/j.ygyno.2021.08.024

      Highlights

      • Combination olaparib and ceralasertib is tolerable at the current RP2D.
      • No RECIST radiological responses occurred and PFS was 4.2 months.
      • PFS was 8.2 months in 3 subjects with BRCA1 mutations.
      • CA-125 responses by GCIG criteria were seen in 3 of 11 evaluable subjects.
      • A signal of activity was seen in DNA repair deficient platinum resistant HGSOC.

      Abstract

      Objective

      Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort.

      Methods

      A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1–7 and olaparib 300 mg orally twice daily, days 1–28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients.

      Results

      Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5–8.2) and 8.2 months (3.6 months–not determined) for patients with BRCA1 mutations.

      Conclusions

      Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.

      Keywords

      1. Introduction

      Platinum-resistant, high-grade serous ovarian cancer (HGSOC, including ovarian, fallopian tube, and primary peritoneal cancer) recurs within 6 months of platinum-based chemotherapy and is associated with a uniformly poor prognosis. Non-investigational treatment options for patients with platinum-resistant ovarian cancer are limited largely to sequential cytotoxic agents with response rates of about 10–30% [
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      ]. The development of effective and tolerable agents to treat patients with platinum-resistant ovarian cancer represents a critical unmet need.
      Targeted inhibitors of poly-ADP ribose polymerase (PARP) are effective in multiple cancers that have deficiencies in DNA repair mechanisms leading to FDA approval for a variety of indications [
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      ]. PARP inhibitors (PARPi) including niraparib, olaparib and rucaparib, which are approved in earlier-line HGSOC settings, are also approved for recurrent platinum-resistant disease in the context of homologous recombination deficiency (HRD) or pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) [
      • Kaufman B.
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      Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
      ,
      • Moore K.N.
      • Secord A.A.
      • Geller M.A.
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      Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.
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      • Oza A.M.
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      Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from study 10 and ARIEL2.
      ]; however, these drugs are most active in platinum-sensitive disease.
      The primary mechanism of action of PARPi is trapping of PARP1 onto single-stranded DNA breaks, preventing DNA repair [
      • Lord C.J.
      • Ashworth A.
      PARP inhibitors: synthetic lethality in the clinic.
      ]. Persistent single-stranded DNA breaks are converted into double-stranded breaks during the process of DNA replication. In cancers with BRCA1/2 pathogenic variants and HRD, the failure to accurately repair double-stranded DNA breaks leads to lethal insult to genomic integrity, constituting the biologic basis for clinically observed responses to PARP inhibition [
      • Helleday T.
      The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings.
      ,
      • Murai J.
      • Huang S.Y.
      • Das B.B.
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      Trapping of PARP1 and PARP2 by clinical PARP inhibitors.
      ]. In patients with HGSOC, PARPi have demonstrated unprecedented improvements in progression-free and overall survival [
      • Coleman R.L.
      • Oza A.M.
      • Lorusso D.
      • et al.
      Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Gonzalez-Martin A.
      • Pothuri B.
      • Vergote I.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian Cancer.
      ,
      • Moore K.
      • Colombo N.
      • Scambia G.
      • et al.
      Maintenance Olaparib in patients with newly diagnosed advanced ovarian Cancer.
      ,
      • Moore K.N.
      • Secord A.A.
      • Geller M.A.
      • et al.
      Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.
      ,
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
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      Olaparib plus Bevacizumab as first-line maintenance in ovarian Cancer.
      ] in the upfront maintenance and relapsed settings, most significantly within the BRCA1/2 mutant and/or HRD population. However, responses to PARPi monotherapy in recurrent disease are rarely complete [
      • Gelmon K.A.
      • Tischkowitz M.
      • Mackay H.
      • et al.
      Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
      ,
      • Kaufman B.
      • Shapira-Frommer R.
      • Schmutzler R.K.
      • et al.
      Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
      ,
      • Audeh M.W.
      • Carmichael J.
      • Penson R.T.
      • et al.
      Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
      ], are less frequent in the 50% of homologous recombination proficient cancers [
      • Cancer Genome Atlas Research N
      Integrated genomic analyses of ovarian carcinoma.
      ], and are seen primarily in individuals with platinum-sensitive disease [
      • Fong P.C.
      • Yap T.A.
      • Boss D.S.
      • et al.
      Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.
      ]. PARPi monotherapy has limited utility in unselected platinum-resistant ovarian cancer patients, with response rates of 4–13% when HRD status is negative or unknown [
      • Gelmon K.A.
      • Tischkowitz M.
      • Mackay H.
      • et al.
      Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
      ,
      • Moore K.N.
      • Secord A.A.
      • Geller M.A.
      • et al.
      Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.
      ,
      • Swisher E.M.
      • Kwan T.T.
      • Oza A.M.
      • et al.
      Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (parts 1 and 2).
      ,
      • Vanderstichele A.
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      • Concin N.
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      • Neven P.
      • Busschaert P.
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      Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.
      ] and approximately 10%–38% in platinum-resistant cancers with HRD [
      • Moore K.N.
      • Secord A.A.
      • Geller M.A.
      • et al.
      Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.
      ,
      • Swisher E.M.
      • Kwan T.T.
      • Oza A.M.
      • et al.
      Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (parts 1 and 2).
      ,
      • Vanderstichele A.
      • Han S.
      • Concin N.
      • Van Gorp T.
      • Berteloot P.
      • Neven P.
      • Busschaert P.
      • Lambrechts D.
      • Vergote I.
      Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.
      ]. Thus, responses to PARPi monotherapy in unselected patients with platinum-resistant disease are infrequent and of limited duration, warranting the development of rational combination strategies to augment efficacy.
      Targeted inhibitors of ATR (ataxia telangiectasia and Rad-3) kinase have also been of interest in HGSOC due to the central role of ATR in the DNA damage response and the increased replication stress seen in these cancers [
      • Lecona E.
      • Fernandez-Capetillo O.
      Targeting ATR in cancer.
      ,
      • Yap T.A.
      • Tan D.S.
      • Terbuch A.
      • et al.
      First-in-Human Trial of the Oral Ataxia Telangiectasia and Rad3-Related Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors.
      ,
      • Weber A.M.
      • Ryan A.J.
      ATM and ATR as therapeutic targets in cancer.
      ,
      • Blackford A.N.
      • Jackson S.P.
      ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response.
      ]. Amplification of CCNE1 in approximately 20% and HR alterations in approximately 50% of HGSOC [
      • Cancer Genome Atlas Research N
      Integrated genomic analyses of ovarian carcinoma.
      ,
      • Ceccaldi R.
      • O’Connor K.W.
      • Mouw K.W.
      • et al.
      A unique subset of epithelial ovarian cancers with platinum sensitivity and PARP inhibitor resistance.
      ,
      • Mouw K.W.
      • D’Andrea A.D.
      • Konstantinopoulos P.A.
      Nucleotide excision repair (NER) alterations as evolving biomarkers and therapeutic targets in epithelial cancers.
      ] also contribute to replication stress and impaired DNA repair in HGSOC. ATR regulates cellular responses to stalled and collapsed replication forks through downstream activation of the CHK1/WEE1 axis. ATR also phosphorylates multiple proteins involved in HR including RAD51 [
      • Curtin N.J.
      DNA repair dysregulation from cancer driver to therapeutic target.
      ,
      • Karnitz L.M.
      • Zou L.
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      ]. Blockade of the ATR/CHK1 pathway results in inappropriate cell cycle progression, chromosomal aberrations, mitotic catastrophe, and ultimately apoptosis [
      • Huntoon C.J.
      • Flatten K.S.
      • Wahner Hendrickson A.E.
      • et al.
      ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status.
      ,
      • Bartek J.
      • Lukas J.
      Chk1 and Chk2 kinases in checkpoint control and cancer.
      ]. Thus, cancers such as HGSOC with high levels of genomic instability and ubiquitous loss of TP53 leading to high levels of replication stress may be especially sensitive to ATR inhibitors (ATRi). Indeed, berzosertib recently demonstrated activity in platinum-resistant high-grade serous ovarian cancer as monotherapy or when combined with cytotoxic chemotherapy [
      • Konstantinopoulos P.A.
      • Cheng S.C.
      • Wahner Hendrickson A.E.
      • et al.
      Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.
      ,
      • Yap T.A.
      • Tan D.S.P.
      • Terbuch A.
      • et al.
      First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors.
      ,
      • Yap T.A.
      • O’Carrigan B.
      • Penney M.S.
      • et al.
      Phase I trial of first-in-class ATR inhibitor M6620 (VX-970) as Monotherapy or in combination with carboplatin in patients with advanced solid tumors.
      ].
      Given the unique mechanisms by how ATR and PARP enzymes each safeguard genomic integrity, there is a strong biologic rationale for combined PARP and ATR inhibition as a way to exploit synthetic lethality in HGSOC with and without HRD. In cell line and patient-derived xenograft models, PARPi treatment resulted in early activation of the ATR/CHK1 pathway and combination PARPi with olaparib, and ATRi with ceralasertib, synergistically suppressed BRCA1/2 mutant HGSOC growth [
      • Kim H.
      • George E.
      • Ragland R.
      • et al.
      Targeting the ATR/CHK1 Axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian Cancer models.
      ,
      • Kim H.
      • Xu H.
      • George E.
      • et al.
      Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models.
      ]. Further, we have shown that combination PARP and ATR inhibition decreased survival and increased cancer regressions in PARPi and platinum-resistant BRCA1/2 mutant (including models with BRCA1/2 reversions) and platinum-resistant CCNE1-amplified cells and PDX ovarian cancer models [
      • Kim H.
      • Xu H.
      • George E.
      • et al.
      Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models.
      ,
      • Yazinski S.A.
      • Comaills V.
      • Buisson R.
      • et al.
      ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells.
      ], supporting the evaluation of this combination in a signal-seeking study of patients with platinum-resistant HGSOC who have limited therapeutic options.
      Ceralasertib (AZD6738), a potent, selective ATRi, is under evaluation as monotherapy and in combination with chemotherapy, ionizing radiation, immunotherapy and other anti-cancer drugs, including PARPi in a variety of genetic contexts (clinicaltrials.gov) []. Olaparib is a PARPi that has demonstrated progression-free and overall survival benefit for patients with HGSOC [
      • Gelmon K.A.
      • Tischkowitz M.
      • Mackay H.
      • et al.
      Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
      ,
      • Kaufman B.
      • Shapira-Frommer R.
      • Schmutzler R.K.
      • et al.
      Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
      ,
      • Ledermann J.
      • Harter P.
      • Gourley C.
      • et al.
      Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
      ,
      • Moore K.
      • Colombo N.
      • Scambia G.
      • et al.
      Maintenance Olaparib in patients with newly diagnosed advanced ovarian Cancer.
      ] and is currently FDA-approved in both the primary and recurrent settings. Combination ceralasertib and olaparib was first evaluated in Study 4, a phase IB clinical trial, that showed this combination was tolerable and identified the recommended phase 2 dose (RP2D) as ceralasertib 160 mg daily on days 1–7 and olaparib 300 mg twice daily on days 1–28 of a 28 day cycle [
      • Krebs M.L.
      • El-Khoueiry A.
      • Bang Y.
      • Postel-Vinay S.
      • Abida W.
      • Carter L.
      • Xu W.
      • Im S.
      • Pierce A.
      • Frewer P.
      • Berges A.
      • Cheung S.Y.A.
      • Stephens C.
      • Felicetti B.
      • Dean E.
      • Hollingsworth S.
      Abstract CT026: Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14–18; Chicago, IL.
      ]. Based on data from this earlier trial, this selected dose and schedule of ceralasertib achieved target exposure >IC90 ATR inhibition for 12 h per day at a steady state in 80% of patients, when combined with the FDA approved standard monotherapy dose of olaparib. CAPRI (Combination ATR and PARP Inhibitor; NCT03462342) is a phase II signal-seeking investigator-initiated study to examine the combination of ceralasertib plus olaparib in subjects with recurrent HGSOC in three cohorts: Cohort A, platinum-sensitive disease; Cohort B, platinum-resistant disease (both A and B independent of HR status); and Cohort C, platinum-sensitive disease that has progressed after PARP inhibitor treatment in HR deficient patients. Here, we summarize the clinical findings from Cohort B (genetically unselected recurrent platinum-resistant HGSOC).

      2. Patients and methods

      2.1 Patient selection and eligibility criteria

      Subjects were enrolled from the outpatient gynecologic and medical oncology practices at the University of Pennsylvania and Johns Hopkins School of Medicine. Eligible patients had recurrent high-grade serous ovarian, primary peritoneal and/or fallopian tube cancer that was deemed platinum-resistant, defined as imaging-based recurrence ≤6 months from the completion of prior platinum-based chemotherapy. All subjects had measurable disease, an ECOG performance status of 0 or 1, and adequate renal (creatinine clearance ≥51 ml/min), hepatic, cardiac, and bone marrow function. Genetic testing (germline sequencing, somatic sequencing, and homologous recombination status testing) was not required for study enrollment. Subjects were required to be at least 3 weeks from prior systemic or radiation therapy and at least 4 weeks from major surgery. Subjects could not have persistent grade ≥ 2 adverse events related to prior treatment with the exception of alopecia and grade 2 peripheral neuropathy. Eligible subjects may not have had more than 3 prior cytotoxic therapies since the development of platinum resistance. Prior PARPi treatment for recurrent disease or maintenance was permitted. Prior ceralasertib or other cell cycle checkpoint inhibitor was not permitted. Patients with known brain metastases diagnosed and treated greater than one year prior to study entry were permitted. Patients with concurrent active malignancies were excluded with the exception of patients with curatively treated stage IA cervical carcinoma, resected stage IA grade 1 endometrial cancer, noninvasive non-melanoma skin cancers, breast ductal carcinoma in situ, or curatively treated solid malignancies or lymphomas with no evidence of disease for >5 years. Willingness to undergo research biopsies was required.
      The clinical trial protocol (see Supplement) was approved by the Institutional Review Boards at both participating sites. All participants provided written informed consent prior to the conduct of any study-related procedures. This trial is registered at Clinicaltrials.gov (NCT03462342). The study was conducted in accordance with the US Food and Drug Administration regulations, the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki.

      2.2 Treatment

      Ceralasertib was administered orally, 160 mg once daily on days 1–7 of a 28-day cycle. Olaparib was administered orally 300 mg twice daily on days 1–28 of a 28-day cycle. Dose reductions or delays were specified in the study protocol, with explicit allowance for treating investigators to employ more conservative reductions or delays as per their discretion. Patients continued on study treatment until investigator/patient decision to withdraw, intolerable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

      2.3 Study assessments

      Medical history including concomitant medication review, physical examination, performance status assessment, and laboratory studies including hematology, blood chemistries, coagulation studies, and urinalysis were performed at: screening, Cycle 1 Day 1, Cycle 1 Day 7, Cycle 1 Day 15, within 3 days prior to the start of each subsequent cycle, as needed for safety, and 30 days after the patient's last dose of study drug. An electrocardiogram was required at screening as well as within 24 h of taking study drug on Cycle 1 Day 1, Cycle 1 Day 15 and on Day 1 of each subsequent cycle. Genetic testing (germline, somatic, and homologous recombination status) that was performed clinically by CLIA-approved laboratories was reviewed and classification of variants' pathogenicity was based on those reports. All homologous recombination testing was performed through Myriad's Genomic Instability Status test utilizing an HRD score ≥ 42 to indicate presence of genomic instability [
      • Telli M.L.
      • Timms K.M.
      • Reid J.
      • et al.
      Homologous recombination deficiency (HRD) score predicts response to platinum-containing Neoadjuvant chemotherapy in patients with triple-negative breast Cancer.
      ].

      2.4 Toxicity evaluation

      Toxicities were graded and recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Toxicity management was described in the protocol and included mitigation measures such as treatment interruption, dose reduction, and blood product transfusion. Prolonged (>4 week) hematologic toxicities warranted hematologist consultation and consideration of bone marrow evaluation. Adverse events of special interest (AESI) for olaparib were pre-defined in the protocol as pneumonitis, the development of myelodysplastic syndrome or acute myeloid leukemia, and the development of a second malignancy. There were no AESI for ceralasertib.

      2.5 Response evaluation

      Cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging of the chest, abdomen and pelvis was performed at baseline, after every two cycles until Cycle 4 and every 3 cycles thereafter. The primary efficacy endpoint of this trial was objective response rate (ORR) defined as the proportion of patients with a complete or partial response based on RECIST 1.1 criteria [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      ]. The secondary endpoint was progression-free survival (PFS) defined as the time from starting treatment to the time of disease progression based on RECIST criteria, or in the absence of this, either disease progression, death, or last follow-up. Cancer antigen 125 (CA-125) tumor marker results were assessed according to Gynecologic Cancer InterGroup (GCIG) criteria [
      • Rustin G.J.
      • Quinn M.
      • Thigpen T.
      • et al.
      Re: new guidelines to evaluate the response to treatment in solid tumors (ovarian cancer).
      ].

      2.6 Statistical considerations

      A Simon optimal two-stage design was employed for the cohort of patients with platinum-resistant HGSOC to test the null hypothesis of ORR of 5% against the alternative that an ORR of at least 20% would warrant further study, under a 10% alpha level and with 90% power. The efficacy evaluable set included subjects who initiated treatment and had at least one response evaluation available. The first stage would enroll 12 evaluable patients. If less than 1 response was observed, then the trial for this cohort would be terminated. If 1 or greater response was observed, an additional 25 patients would be enrolled for a total of 37 patients. Under the null hypothesis (5% ORR), the probability of early termination for the platinum-resistant cohort was 54%. Demographic and baseline characteristics were summarized using descriptive statistics. The safety evaluable set included all subjects who initiated treatment. Survival was analyzed using the Kaplan-Meier method. Data cutoff date was June 10, 2020.

      3. Results

      3.1 Patient characteristics

      Between March 2018 and November 2019, 14 patients with recurrent platinum-resistant HGSOC signed study consent, were enrolled into the study, and began treatment. Two subjects withdrew consent within the first 2 weeks of study treatment and thus were evaluable for toxicity but not response. Patient demographics and baseline characteristics are shown in Table 1. Median age of participants was 63 (range 50–74). The majority of patients were White (n = 12, 86%) and 2 patients were Black (14%). Most subjects had an ECOG performance status of 0 (n = 11, 79%). Participants received a median of 2 (range 1–5) prior therapies for advanced HGSOC. All patients had prior platinum and taxane therapy exposure and none received prior PARP inhibitor treatment. Of 14 patients enrolled, all had progressive disease including either progression on penultimate treatment (n = 9) or a new diagnosis of recurrent disease within 6 months of last platinum (n = 5) at the time of study entry.
      Table 1Subject demographics and baseline characteristics.
      CharacteristicN = 14

      N (%) or median (range)
      Age, years63 (50–74)
      Race
      White12 (85.7)
      Black2 (14.3)
      Other0
      ECOG Performance Status
      011 (78.6)
      13 (21.4)
      High grade serous histology14 (100)
      Number of prior systemic therapies (total)2 (1–5)
      No. prior lines of therapy for platinum-resistant recurrent disease
      09 (64)
      13 (21)
      22 (14)
      Platinum-free interval, months4.1 (0.5–6.0)
      Prior PARP inhibitor use0
      Germline Alterations
      BRCA1 pathogenic / likely pathogenic variant1 (7.1)
      BRCA2 pathogenic / likely pathogenic variant0
      Pathogenic / likely pathogenic variant in another HRR
      HRR = homologous recombination repair.
      gene
      0
      No pathogenic/likely pathogenic alterations in HRR genes11 (71.4)
      Germline testing not performed2 (14.3)
      Somatic Alterations
      BRCA1 pathogenic / likely pathogenic variant2 (14.2)
      BRCA2 pathogenic / likely pathogenic variant0
      FANCD2 pathogenic variant1 (7.1)
      No somatic alterations in BRCA1/2 or FANCD29 (64.2)
      Somatic testing not performed2 (14.3)
      Genomic Instability Status
      Positive0
      Negative2 (14.3)
      Not performed
      The subjects with BRCA1 pathogenic variants (1 germline, 2 somatic) were among those in whom Genomic Instability Status testing was not performed.
      12 (85.7)
      low asterisk HRR = homologous recombination repair.
      low asterisklow asterisk The subjects with BRCA1 pathogenic variants (1 germline, 2 somatic) were among those in whom Genomic Instability Status testing was not performed.

      3.2 Germline and tumor molecular profiling

      Available data from clinically performed genetic testing are shown in Table 2. One patient had a pathogenic germline variant in BRCA1 and two had deleterious somatic BRCA1 variants. A fourth patient had a somatic mutation in FANCD2. An additional two patients who had genomic instability status (GIS) testing were found to be GIS negative indicating HR proficiency.
      Table 2Genetic and HRD testing: Summary of germline sequencing, somatic sequencing, and assays evaluating for HRD for all subjects.
      Subject #Germline MPT
      MPT = multigene panel testing, including ATM, BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, PALB2, MLH1, MSH2, MSH6, PMS2, EPCAM (deletion/duplication), unless otherwise stated.
      Somatic HRR gene alterations
      HRR genes included BRCA1, BRCA2, ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D.
      HRD results and assayAdditional somatic alterations of interest and assay
      Somatic alterations of interest include mutations in or amplification of CCNE1, PIK3CA, PTEN; CCNE1 not reported in somatic testing: 109, 114; PIK3CA not reported in somatic testing: 126; PTEN not reported in somatic testing: 102, 114.
      130Not performedNoneNot performedNoneCARIS MI Profile
      122NoneNoneGIS negativeMyriad Genomic Instability Status Test
      Presence of genomic instability defined as HRD score ≥ 4247.
      PIK3CA Exon 10 p.E545KCARIS MI Profile
      109NoneNoneNot performedNoneCARIS MI Profile
      126Not performedNoneNot performedNoneCARIS MI Profile
      102NoneNoneGIS negativeMyriad Genomic Instability Status Test
      Presence of genomic instability defined as HRD score ≥ 4247.
      NoneCARIS MI Profile
      119NoneNot performedNot performedNoneCARIS MI Profile
      116NoneNoneNot performedNoneFoundation One
      107BRCA1

      c.4936del (p.Val1646Serfs*12)
      Not performedNot performedNot performed
      127NoneBRCA1

      Exon 18

      c.5175_5193 + 4del23
      Not performedNoneCARIS MI Profile
      202NoneBRCA1

      Exon 10 p.C328fs
      Not performedNoneCARIS MI Profile
      114None
      Documentation of specific testing performed not available.
      NoneNot performedNoneCARIS MI Profile
      111None
      ATM and PALB2 not included on panel.
      FANCD2

      Exon 6 c.378-2A > C
      Not performedNoneCARIS MI Profile
      118None
      ATM, PALB2, RAD51C, RAD51D, BRIP1 not included on panel.
      Not performedNot performedNot performed
      131NoneNone
      Documentation of specific testing performed not available.
      Not performedNoneFoundation One
      1 MPT = multigene panel testing, including ATM, BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, PALB2, MLH1, MSH2, MSH6, PMS2, EPCAM (deletion/duplication), unless otherwise stated.
      2 HRR genes included BRCA1, BRCA2, ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D.
      3 Somatic alterations of interest include mutations in or amplification of CCNE1, PIK3CA, PTEN; CCNE1 not reported in somatic testing: 109, 114; PIK3CA not reported in somatic testing: 126; PTEN not reported in somatic testing: 102, 114.
      4 Presence of genomic instability defined as HRD score ≥ 4247.
      5 Documentation of specific testing performed not available.
      6 ATM and PALB2 not included on panel.
      7 ATM, PALB2, RAD51C, RAD51D, BRIP1 not included on panel.

      3.3 Adverse events and dose modifications

      All 14 patients who received study therapy were evaluable for toxicity and were included in the safety analysis. Adverse events (AEs) possibly, probably, or definitely related to study therapy are shown in Table 3. Most AEs were grade 1/2 and medically manageable. Although hematological events are a known toxicity with olaparib and ceralasertib, only 1 patient experienced a grade 3 hematological toxicity (anemia). The majority of patients reported fatigue (grade 1/2: 71.4%; grade 3: 7.1%) and nausea (grade 1/2: 50.0%; grade 3: 14.3%). Fifty percent of treated patients reported anorexia that was largely grade 1 or 2. Gastrointestinal adverse events generally appeared within the first 2 weeks of therapy and improved in severity over the course of the first two cycles of study therapy. There were no grade 4/5 AEs. One serious adverse event, pleural effusion leading to hospitalization after consent but prior to starting study drug, occurred on study and was unrelated to investigational therapy. No AESI for olaparib occurred on study.
      Table 3Adverse events: Summary of AEs occurring in ≥1 subject possibly, probably, or definitely related to study treatment (n = 14 subjects).
      Adverse EventG1/2 (# pts, %)G3 (# pts, %)Total (# pts, %)
      Fatigue10 (71.4)1 (7.1)11 (78.6)
      Nausea7 (50.0)2 (14.3)9 (64.2)
      Anorexia6 (42.9)1 (7.1)7 (50.0)
      Dysgeusia6 (42.9)06 (42.9)
      Vomiting5 (35.7)05 (35.7)
      Anemia3 (21.4)1 (7.1)4 (28.6)
      Dizziness4 (28.6)04 (28.6)
      Generalized muscle weakness4 (28.6)04 (28.6)
      Abdominal pain4 (28.6)04 (28.6)
      Dyspnea4 (28.6)04 (28.6)
      Dyspepsia3 (21.4)03 (21.4)
      Creatinine increased2 (14.3)02 (14.3)
      Diarrhea2 (14.3)02 (14.3)
      Platelet count decreased1 (7.1)01 (7.1)
      *No grade 4–5 events occurred on study.
      Five (36%) patients out of 14 had dose reductions (DR) due to toxicity. Three had an olaparib DR, one had a ceralasertib DR, and one patient had DR of both drugs. Of the 3 patients with olaparib DR, two had dose reductions to olaparib 200 mg orally twice daily due to asymptomatic reduction in creatinine clearance to <51 and one subject had a dose reduction in olaparib to 250 mg orally twice daily due to grade 3 fatigue. Ceralasertib administration was modified from 160 mg daily on days 1–7 to 160 mg daily on days 1–4 in one subject due to hematologic toxicity, with grade 2 thrombocytopenia and grade 2 anemia noted at her Cycle 1 Day 15 visit, and improvement noted after dose modification. Finally, one subject had dose reductions of both olaparib and ceralasertib (250 mg orally twice daily and 120 mg orally daily on days 1–7) due to grade 3 nausea and grade 3 anorexia.
      Two subjects withdrew from study, both within the first 2 weeks of therapy. One subject discontinued study medication on Cycle 1 Day 10 of therapy due to grade 2 fatigue and anorexia as well as difficulty commuting to the treating facility. A second subject reported grade 3 nausea, grade 2 anorexia, and grade 2 abdominal pain during the first few days of study therapy and discontinued study therapy on Cycle 1, Day 5 desiring to change treatment to standard chemotherapy. Neither of the two subjects who withdrew from study were willing to consider dose modifications, anti-emetics, or other symptomatic therapy prior to study withdrawal.

      3.4 Response

      Twelve patients who completed 1 cycle of study therapy and had a disease assessment on study were evaluable for response. There were no partial or complete objective responses by RECIST v1.1 in the first 12 evaluable patients so the platinum-resistant cohort did not proceed to second stage. Best response as well as duration on study are shown in a waterfall plot (Fig. 1). Best overall response by RECIST v1.1 was stable disease achieved in 9 patients and progression of disease in 3 patients. Median progression-free survival was 4.2 months (90% CI: 3.5,8.2) for all subjects (Fig. 2). The 3 subjects with germline or somatic BRCA1 mutations had PFS events at 8.2, 9.8, and 3.6 months respectively, yielding a median PFS of 8.2 months (90% CI: 3.6 – not determined).
      Fig. 1
      Fig. 1Waterfall plot of best response (as assessed by RECIST).
      Among 12 patients evaluable for response on study, best objective response achieved was stable disease in 9 subjects and disease progression in 3 subjects (#116 had progression based on a new lesion).
      Fig. 2
      Fig. 2Kaplan-Meier curve of progression-free survival in all patients evaluable for response.
      Progression-free survival in all patients evaluable for response was 4.2 months (90% CI:3.5–8.2).
      Although no objective responses by RECIST v1.1 were seen, five of 12 subjects (42%) had reductions in disease burden between 20% and < 30% (Fig. 1). These included the 2 subjects with somatic BRCA1 pathogenic variants, 1 subject with a germline BRCA1 pathogenic variant, and 1 subject with a somatic FANCD2 mutation. Of these 5 subjects, 3 underwent dose reductions of olaparib. One subject who had no germline or somatic genetic alterations found on sequencing achieved a 26% reduction in disease burden and remained on study for 15 cycles. Homologous recombination testing results are unavailable for this subject.
      Of the twelve patients evaluable for response by RECIST v1.1, 11 were evaluable by GCIG criteria, with one subject not evaluable due to baseline CA-125 not elevated to twice the upper limit of normal. On the basis of GCIG criteria, 3/11 (27%) patients (subjects 127, 114, 202) had responses to treatment, with declines in CA-125 of more than 50% (Fig. 3). This included 2 patients with normalization of CA-125. Two of the patients with CA-125 responses had somatic BRCA1 mutations, including one of the two with CA-125 normalization. The maximum decline in CA-125 was 99% in Patient 127, from 4408 units/ml (u/mL) at baseline to 59 u/mL on Cycle 6, Day 1. This patient's GCIG response was achieved by Cycle 2 of therapy. Evidence of biochemical activity was concordant with imaging, with these 3 patients having a ≥ 20% reduction of tumor burden by RECIST v1.1. Although two of the 3 subjects with CA-125 responses were minimally symptomatic at the start of study therapy, evidence of biochemical activity was also accompanied by an improvement in symptoms in Patient 127. This patient had baseline dyspnea associated with a malignant pleural effusion that markedly improved on study. She also had a decrease in frequency of thoracenteses while on study; she required thoracenteses on Cycle 1, Day 1 and Cycle 1, Day 11, and then did not require a repeat thoracentesis until Cycle 5, Day 8. She required no subsequent thoracenteses during the remainder of her >5 months on study.
      Fig. 3
      Fig. 3Best percentage change in CA-125 from baseline.
      Three subjects had an elevated CA-125 at baseline with a reduction of >50% while on therapy that was sustained for >28 days. Two subjects (202 and 114) had normalization of CA-125.

      4. Discussion

      This pilot signal-finding study (CAPRI cohort B) evaluating combination olaparib and ceralasertib at the current RP2D (ceralasertib 160 mg PO on days 1–7 and olaparib 300 mg PO BID continuously), in an unselected platinum-resistant HGSOC population, did not yield objective responses. The primary endpoint of this study was response rate on the basis of RECIST v1.1. The threshold for this cohort proceeding onto stage II of this study was one or more responses in 12 evaluable patients; this threshold was not met. Disease stability was achieved in the majority of subjects enrolled, even though immediately prior to study enrollment, all patients had disease progression (Fig. 1). The secondary efficacy endpoint was PFS. In the overall study population, median PFS was 4.2 months. Importantly, at the current dose and schedule, this combination was tolerable with toxicity that was largely grade 1 or 2 and medically manageable. The adverse event profile of combination therapy was qualitatively similar to the toxicity profile of single-agent olaparib, with fatigue and nausea being the most common adverse events seen in the present combination study and in olaparib monotherapy studies [
      • Ledermann J.
      • Harter P.
      • Gourley C.
      • et al.
      Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
      ,
      • Domchek S.M.
      • Aghajanian C.
      • Shapira-Frommer R.
      • et al.
      Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy.
      ,
      • Matulonis U.A.
      • Penson R.T.
      • Domchek S.M.
      • et al.
      Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.
      ,
      • Pujade-Lauraine E.
      • Ledermann J.A.
      • Selle F.
      • et al.
      Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.
      ].
      There was however, a signal of clinical activity based on cancer regression by imaging and GCIG response, particularly but not exclusively in subjects with HR deficient platinum-resistant recurrent HGSOC. Five of 12 (42%) evaluable subjects achieved a decrease in tumor burden of between 20% and < 30% (Fig. 1) including four subjects with BRCA1 and FANCD2 mutations. The fifth subject, who was germline BRCA1/2 wild-type with unknown HRD cancer status had a 26% tumor regression with time on treatment of 15 months. Also, three subjects (27%; two with BRCA1 mutations) evaluable by GCIG criteria (n = 11) had CA-125 responses, one with significant improvement in symptoms (Fig. 3). When the subjects with germline or somatic pathogenic BRCA1 variants are examined, the median PFS was 8.2 months (range: 3.6 months – not determined). Although no responses were seen, there appears to be a signal of activity most evident in HR deficient HGSOCs in this small platinum-resistant cohort.
      Preclinical data evaluating this combination similarly showed activity in specific genetic contexts [
      • Kim H.
      • George E.
      • Ragland R.
      • et al.
      Targeting the ATR/CHK1 Axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian Cancer models.
      ,
      • Kim H.
      • Xu H.
      • George E.
      • et al.
      Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models.
      ,
      • Yazinski S.A.
      • Comaills V.
      • Buisson R.
      • et al.
      ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells.
      ]. BRCA1/2 mutant (including BRCA1/2 reversion) PARPi and platinum-resistant cells and CCNE1 amplified platinum-resistant cells have significantly elevated levels of baseline pATR/pCHK1 compared to drug sensitive cells suggesting a dependency on this pathway for survival. Indeed, the addition of ATRi re-sensitizes these resistant models to PARP inhibition leading to synergy with increased replication fork stalling, DNA double stand breaks, and apoptosis. This combination demonstrates activity in selected genetic contexts demonstrating high levels of replication stress and dependency on ATR/CHK1 [
      • Kim H.
      • George E.
      • Ragland R.
      • et al.
      Targeting the ATR/CHK1 Axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian Cancer models.
      ,
      • Kim H.
      • Xu H.
      • George E.
      • et al.
      Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models.
      ,
      • Yazinski S.A.
      • Comaills V.
      • Buisson R.
      • et al.
      ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells.
      ]. These data formed the foundation of the current clinical trial; however, as CAPRI cohort B is a pilot signal-finding study evaluating combination olaparib and ceralasertib, an unselected platinum-resistant HGSOC population was used, and subjects were enrolled irrespective of germline or somatic molecular profile.
      Single agent PARP inhibitors have demonstrated some activity in platinum-resistant, genetically unselected ovarian cancers. Overall response rates (ORR) of 18% and 12% were seen in CLIO and ARIEL 2 [
      • Swisher E.M.
      • Kwan T.T.
      • Oza A.M.
      • et al.
      Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (parts 1 and 2).
      ,
      • Vanderstichele A.
      • Han S.
      • Concin N.
      • Van Gorp T.
      • Berteloot P.
      • Neven P.
      • Busschaert P.
      • Lambrechts D.
      • Vergote I.
      Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.
      ], respectively. Our overall median PFS of 4.2 months in the CAPRI platinum-resistant cohort is longer than the 2.9 month PFS seen in the CLIO trial with olaparib single-agent (n = 67 patients) for platinum-resistant HGSOC [
      • Vanderstichele A.
      • Han S.
      • Concin N.
      • Van Gorp T.
      • Berteloot P.
      • Neven P.
      • Busschaert P.
      • Lambrechts D.
      • Vergote I.
      Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.
      ], and the 1.9 month and 1.8 month PFSs seen with rucaparib in platinum-resistant/refractory BRCA1/2 wild-type HGSOCs that are LOH-high and LOH-low, respectively [
      • Swisher E.M.
      • Kwan T.T.
      • Oza A.M.
      • et al.
      Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (parts 1 and 2).
      ]. Overall PFS for our study is also similar to the 4.8 month PFS seen with mirvetuximab soravtansine, a folate receptor alpha antibody drug conjugate [
      • Moore K.N.
      • Martin L.P.
      • O’Malley D.M.
      • et al.
      Safety and activity of Mirvetuximab Soravtansine (IMGN853), a Folate receptor alpha-targeting antibody-drug conjugate, in platinum-resistant ovarian, fallopian tube, or primary peritoneal Cancer: a phase I expansion study.
      ]. A PFS of 4.2 months is also comparable to cytotoxic monotherapies including pegylated liposomal doxorubicin, weekly paclitaxel or topotecan as monotherapy with a PFS of 3.4 months as single agents for platinum-resistant HGSOC. However, the PFS seen with combination olaparib and ceralasertib is less than the 6.7 month PFS seen with chemotherapy in combination with bevacizumab in the AURELIA trial [
      • Pujade-Lauraine E.
      • Hilpert F.
      • Weber B.
      • et al.
      Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial.
      ], which is often considered a standard of care for patients with platinum-resistant ovarian cancer.
      Given that enrolled patients had no prior treatment with PARP inhibitor monotherapy, is in unclear whether the signal of activity for olaparib plus ceralasertib was in fact driven by olaparib alone. PARP inhibitor monotherapies show improved responses and PFS in BRCA1/2 mutant compared to BRCA1/2 wildtype platinum-resistant HGSOCs. In Study 42, olaparib treatment in BRCA1/2 mutant platinum-resistant HGSOCs, demonstrated an ORR of 13–39% (lower response correlated with ≥6 regimens) and PFS of 5.5 months [
      • Domchek S.M.
      • Aghajanian C.
      • Shapira-Frommer R.
      • et al.
      Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy.
      ]. The CLIO study reported an ORR of 38% in BRCA1/2 mutant platinum-resistant HGSOC; PFS not yet reported [
      • Vanderstichele A.
      • Han S.
      • Concin N.
      • Van Gorp T.
      • Berteloot P.
      • Neven P.
      • Busschaert P.
      • Lambrechts D.
      • Vergote I.
      Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.
      ]. Part 2 of the ARIEL2 study noted an ORR of 23% and PFS of 7.2 months for rucaparib treatment in BRCA1/2 associated platinum-resistant or refractory HGSOC treated with rucaparib [
      • Swisher E.M.
      • Kwan T.T.
      • Oza A.M.
      • et al.
      Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (parts 1 and 2).
      ]. In QUADRA, the ORR was 27% in BRCA1/2 mutated platinum-resistant or refractory HGSOC (median PFS for this subgroup not reported) [
      • Moore K.N.
      • Secord A.A.
      • Geller M.A.
      • et al.
      Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.
      ]. Thus, higher response rates have been seen in larger studies evaluating olaparib, rucaparib and niraparib monotherapy in BRCA1/2 mutant platinum-resistant or refractory HGSOC than in the present study which included 3 patients with HRD-associated HGSOC and one patient with a somatic mutation in FANCD2, a homologous recombination repair gene. Although, the median PFS of 8.2 months for BRCA1 mutant, platinum-resistant patients seen in our pilot study appears to be higher than olaparib and rucaparib monotherapy, the observed tumor burden reductions seen in patients with BRCA1 mutations may indeed have been driven by olaparib.
      Several factors may explain why deeper tumor regressions were not seen in our study. First, the study population was genomically unselected in order to capture signals of activity rather than specifically study the population most likely to respond based on preclinical data. Responses may have been observed if patients were enriched for BRCA1/2 and/or CCNE1 amplified ovarian cancers. Second, providers used more conservative dose reductions and treatment holds and dose re-escalation was not permitted. Two subjects with somatic BRCA1 pathogenic variants had dose reductions of olaparib, one for asymptomatic increase in creatinine, and another for fatigue. Four of 5 subjects who had dose reductions still experienced stable disease on study, with 3 of 5 subjects experiencing ≥20% reductions in tumor burden.
      Importantly, another possibility for the lack of deeper tumor regressions seen with combination is that the dose and schedule for this combination was not optimal. Our in vitro and PDX studies show increased drug activity when drugs are given concurrently and involve higher doses of ATR inhibition and slightly lower doses of PARP inhibition. The dose and schedule of the combination studied in the current trial was determined in Study 4 as the RP2D (Recommended phase 2 dose) [
      • Krebs M.L.
      • El-Khoueiry A.
      • Bang Y.
      • Postel-Vinay S.
      • Abida W.
      • Carter L.
      • Xu W.
      • Im S.
      • Pierce A.
      • Frewer P.
      • Berges A.
      • Cheung S.Y.A.
      • Stephens C.
      • Felicetti B.
      • Dean E.
      • Hollingsworth S.
      Abstract CT026: Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14–18; Chicago, IL.
      ], using a fixed standard dose of olaparib for a PARP inhibitor naïve population. Attempts to extend ceralasertib beyond 7 days were not tolerated clinically with olaparib 300 mg BID in the phase I study due to hematologic toxicity. Strategies to increase the duration or dose of ceralasertib, concomitant with lower doses of olaparib to improve efficacy in patients with PARPi resistance are currently being explored in expansion cohorts in CAPRI in collaboration with the Dana Farber Cancer Institute (Inter SPORE collaboration, NCT03462342) and Study 4 (NCT02264678). Pharmacodynamic and translational studies were performed as part of the present trial and will be reported in sum for the platinum-resistant and PARPi-resistant cohorts. These data are critical for biomarker identification to guide patient selection and inform additional dosing strategies for future studies evaluating this combination.
      In summary, treatment with combination olaparib and ceralasertib was safe and yielded signals of therapeutic activity most notably in the subset of individuals with germline or somatic pathogenic variants in BRCA1. Selection of a patient population on the basis of genetic context (presence of BRCA1/2 and CCNE1 amplification) may yield greater activity. Given these preliminary findings, the current clinical trial supports further exploration of the combination of olaparib and ceralasertib in patients with platinum-resistant HGSOC, with a focus on treating cancers with DNA repair deficiency.

      Declaration of Competing Interest

      F.S. serves on a scientific advisory board and has received funding for clinical trials from AstraZeneca; R.D. reports personal fees from Repare Therapeutics, advisory role at VOC Health; D.T. reports other from Quantitative Radiology Solutions LLC; E.D. and S. S. are employees and stockholders at AstraZeneca; L.M. reports personal fees from Elucida Oncology, Inc., Sutro Biopharma, Inc., GlaxoSmithKline, AstraZeneca, ImmunoGen, other from Agenus, Inc.; P.S. reports grants from AstraZeneca; R.B. reports personal fees from AstraZeneca, Tesaro, Genentech/Roche, Myriad, Agenus, Regeneron, Janssen, Merck, Morphotek, VBL Therapeutics; S.D. reports personal fees from AstraZeneca; S.G. reports grants and personal fees from AstraZeneca and GSK, personal fees from: Immunogen, Sermonix, Elavar Therapeutics, grants from: Abbvie, Pfizer, Rigel, Iovance, Tesaro, Genentech/Roche, PharmaMar.

      Acknowledgements

      Funding is from NIH 5R37CA215436-02 (Simpkins) and SPORE 1P50CA228991 (Simpkins, Drapkin, Ie-Ming Shih), V Foundation (Simpkins, Shah); AstraZeneca #827744. UPENN Biotrust, JHU SPORE Biorepository core led by Dr. Tian-Li Wang.

      Appendix A. Supplementary data

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