Ceralasertib/Olaparib is Active in Recurrent, Platinum-Sensitive, Recurrent Ovarian Cancer Irrespective of HRD Status

Fiona Simpkins, MD

Treatment with the combination of ceralasertib (AZD6738) and olaparib (Lynparza) demonstrated clinical activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer, regardless of homologous recombination deficient (HRD) status, according to data from cohort A of the phase 2 CAPRI trial (NCT03462342) shared at the 2024 ASCO Annual Meeting.¹

Findings showed that patients in cohort A treated with ceralasertib plus olaparib (n = 37) experienced an overall response rate (ORR) of 49% that was comprised of 3 patients with a complete response (CR) and 15 with a partial response (PR). Seventeen patients had stable disease, and 2 had progression of disease.

Furthermore, the ORR was 45% in patients with HRD-negative disease (n = 20), 53% in patients with HRD-positive disease (n = 13), and 50% in patients whose HRD status was unknown (n = 4).

“Ceralasertib [plus] olaparib [demonstrated] clinical activity in [patients with] platinum-sensitive, recurrent high-grade ovarian cancers, irrespective of HRD status,” Fiona Simpkins, MD, stated in a presentation of the data. “[The] combination [was] tolerable with toxicity similar to that of olaparib monotherapy.”

Simpkins is the Hilarie L. and Mitchell L. Morgan President's Distinguished Professor in Women's Health at the Perelman School of Medicine of the University of Pennsylvania, an attending physician, Gynecologic Oncology, in the Department of Ob/Gyn at the Hospital of the University of Pennsylvania and Pennsylvania Hospital, and director of Clinical & Translational Gynecologic Oncology Research at Penn Medicine Health System in Philadelphia.

Previously at the 2021 ASCO Annual Meeting, investigators presented data on cohort C from the CAPRI study, which enrolled patients with platinum-sensitive, HRD-positive, high-grade serous ovarian cancer with acquired resistance to PARP inhibition (n = 12). In this patient population, ceralasertib plus olaparib elicited an ORR of 50% and a median progression-free survival (PFS) of 7.5 months (95% CI, 4.7-15.1).²

CAPRI was an open-label, nonrandomized trial that included 4 cohorts. Cohort A included patients with platinum-sensitive disease who were unselected for HRD and who had not experienced disease progression on prior PARP inhibitors; cohort B featured patients with platinum-resistant disease; cohort C evaluated patients with HRD-positive disease who progressed on a prior PARP inhibitor; and Cohort D was a dose-exploration group. The evaluation presented at the 2024 ASCO Annual Meeting focused on findings from Cohort A.

To be eligible for cohort A, patients needed to be at least 18 years of age with histologically or cytologically confirmed recurrent high-grade serous ovarian, primary peritoneal, and/or fallopian tube cancer with no standard curative measures available. Patients were allowed to have BRCA-unmutated disease or an unknown BRCA mutation status. Patients harboring germline BRCA mutations were allowed to be included in cohort A; however, a maximum of 10 patients with BRCA mutations were allowed to be enrolled in the cohort.³

Other key inclusion criteria included an ECOG performance status of 0 or 1; a life expectancy of at least 6 months; measurable disease per RECIST 1.1 criteria; and adequate renal and hepatic function.

Eligible patients were treated with oral olaparib at 300 twice per day on days 1 through 28 plus oral ceralasertib at 160 mg once per day on days 1 through 7 of each cycle.¹

The primary end point of the trial was ORR and toxicity, and the secondary end point was progression-free survival (PFS). At the trial's interim analysis, which included the first 17 patients enrolled, an ORR of 40% was required to continue enrollment to 37 patients.

Patients in cohort A had a median age of 69 years (range, 48-80), and most were non-Hispanic White (91,9%) and had an ECOG performance status of 0 (62.2%). Patients received either 1 (56.8%), 2 (29.7%), or at least 3 (13.5%) prior lines of systemic therapy; 5.4% of patients received a prior PARP inhibitor. Additionally, patients also had either a platinum-free interval of 6 to 12 months (37.8%) or 12 or more months (62.2%).

Germline testing results revealed that 8.1% of patients had a germline pathogenic or likely pathogenic gene variant present; 89% had no pathogenic mutation detected, and 2.7% did not have testing performed. Regarding HRD status (n = 34), 23.5% of patients were HRD-positive, 5.9% had loss of heterozygosity, 58.8% were HRD-negative, and 11.8% of patients did not have testing performed.

"The median duration on study without progression was 7.3 months [range, 1.6-45.9]," Simpkins reported in the presentation. "There are 6 patients active on study, with 3 being quite early on in treatment.”

The median PFS for all patients in cohort A was 8.4 months (95% CI, 5.79-11.01). In the HRD-positive population, the median PFS was 9.3 months (95% CI, 7.51-11.09); in the HRD-negative population, the median PFS was 7.6 months (95% CI, 6.84-14.51).

Regarding safety, adverse effects (AEs) led to dose reductions of olaparib in 43% of patients; however, no patients required dose reductions of ceralasertib. AEs led to treatment discontinuation in 3% of patients.

The most common any-grade treatment-related AEs (TRAEs) reported in at least 10% of patients included nausea (89%), fatigue (86%), anemia (62%), diarrhea (49%), headache (46%), constipation (41%), vomiting (32%), dysgeusia (30%), lower extremity pain (27%), back pain (27%), dyspnea (24%), anorexia (24%), edema (24%), decreased platelet count (22%), increased creatinine (16%), abdominal pain (16%), hypomagnesemia (14%), dizziness (14%), cough (14%), palpitations (11%), decreased neutrophil count (11%), insomnia (11%), dyspepsia (11%), COVID-19 (11%), and bloating (11%).

Grade 3/4 TRAEs included fatigue (3%), anemia (22%), diarrhea (5%), decreased platelet count (5%), and decreased neutrophil count (5%).

“Future clinical trials evaluating this combination are warranted. Tumor molecular profiling to optimize functional biomarkers of response, such as RAD51 foci, for PARP inhibitor combinations is critical and ongoing,” Simpkins concluded.

References

1. Simpkins F, NasioudisD, Wethington SL, et al. Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-sensitive epithelial ovarian cancer (Cohort A). J Clin Oncol. 2024;42(suppl 16):5510. doi:10.1200/JCO.2024.42.16_suppl.5510
2. Wethington SL, Shah PD, Martin LP, et al. Combination of PARP and ATR inhibitors (olaparib and ceralasertib) shows clinical activity in acquired PARP inhibitor-resistant recurrent ovarian cancer. J Clin Oncol. 2021;39(suppl 15):5516. doi:10.1200/JCO.2021.39.15_suppl.5516
3. Combination ATR and PARP inhibitor (CAPRI) trial with AZD6738 and olaparib in recurrent ovarian cancer (CAPRI). ClinicalTrials.gov. Updated July 1, 2024. Accessed August 1, 2024. https://clinicaltrials.gov/study/NCT03462342