Ceralasertib Shows Clinical Activity With or Without Olaparib in Gynecologic Cancers

Treatment with ceralasertib (AZD6738) alone and in combination with olaparib (Lynparza) led to promising signals of clinical activity in multiple rare gynecologic cancers, according to initial findings from the phase 2 ATARI trial (NCT04065269). These findings were presented at the European Society for Medical Oncology (ESMO) Gynaecologic Cancers Congress 2023.

Although the threshold for response was not met for patients with clear cell carcinoma in this trial, the key secondary end points of duration of response (DOR) and progression-free survival (PFS) at 16 weeks appeared promising for patients with these rare and aggressive gynecologic cancers, including endometrial and ovarian.

Additionally, the non–clear cell basket cohort of the trial (cohort 3) led to an overall response rate (ORR) of 21%, a median DOR of 41 weeks, and a PFS of 54% at 16 weeks with the combination of ceralasertib and olaparib. Although these data show promise for the combination, further research is warranted. “This academic-sponsored international trial is the first evaluating ATR inhibition specifically in nonserous gynecological cancers, and according to ARID1A status. The toxicity profile was manageable, with 6% discontinuing due to adverse events [AEs],” Susana Banerjee, MBBS, MA, PhD, FRCP, consultant medical oncologist and research lead for the Gynecology Unit at The Royal Marsden NHS Foundation Trust in London, said in a presentation of the findings.

ATARI

ATARI is a multicenter, open-label, international, parallel cohort platform, phase 2 trial where investigators assessed ceralasertib in ARID1A-stratified gynecologic cancers to determine whether ceralasertib has single- agent activity alone or in combination with olaparib for this patient population.

Patients with relapsed ovarian clear cell carcinomas or endometrial clear cell carcinomas with ARID1A loss were enrolled into cohort 1A and administered ceralasertib alone at a dose of 160 mg twice a day on days 1 to 14 of each 28-day cycle.

In cohort 2, patients with clear cell carcinomas with no ARID1A loss were enrolled and administered 160 mg of ceralasertib once a day on days 1 to 7, along with olaparib at 300 mg twice daily on days 1 to 23.

Cohort 3 then enrolled patients with other non–clear cell carcinoma histological subtypes, including endometrioid, carcinosarcoma, and cervical, who were given a matching regimen to those in cohort 2.

The primary end point of the study was best ORR per RECIST version 1.1, with secondary end points including disease control rate (DCR) and PFS.

Each of the cohorts used a Simon 2-stage design and recruited 29 patients (P0 = 0.1; P1 = 0.3; α = 5%; 80% power).

A total of 168 patients were registered between November 2019 and April 2022 across 13 sites in the United Kingdom, France, and Canada, including 117 in cohorts 1A and 2, and 42 in cohort 3; 9 patients were screened out. One hundred patients were evaluable for the primary end point analysis. The efficacy results presented at the meeting evaluated the first 29 evaluable patients per each cohort.

Baseline characteristics for the clear cell carcinoma cohorts showed the median age of patients to be 56 years (range, 52-63) in cohort 1A and 60 years (range, 51-69) in cohort 2. Between these cohorts, most patients, 26 (90%) vs 23 (79%, respectively), had ovarian cancer compared with 3 (10%) and 6 (21%) patients who had endometrial cancer. The numbers of prior lines of therapies were 2 for cohort 1A with ARID1A loss and 1 for cohort 2 with no ARID1A loss. This included 7 (24%) and 8 (28%) patients, respectively, who had prior treatment with an antiangiogenic agent and 6 (21%) and 9 (31%) patients who received previous immunotherapy treatment.

In cohort 3 of patients with non–clear cell subtypes, the median age was 61 years (range, 54-68). Three patients (10%) had endometrioid ovarian carcinoma, 8 (28%) had endometrioid endometrial carcinoma, 10 (34%) had cervical cancer, 3 (10%) had ovarian carcinosarcomas, and 5 (17%) had endometrial carcinosarcomas. Twenty- one percent of patients had ARID1A loss, whereas 79% did not.

Regarding safety, grade 3 or greater toxicities were seen in 47% of patients in cohort 1A (n = 36), 41% in cohort 2 (n = 32), and 39% in cohort 3 (n = 33). Anemia was the most common grade 3 or greater treatment-related AE, at 36% with the monotherapy and 23% with the combination. All other grade 3 toxicities observed were less than 10%, including cytopenias. Additionally, discontinuation rates that resulted from AEs were 10% in all cohorts.

For efficacy, cohort 1A showed an ORR of 14%, with a median DOR of 24 weeks (IQR, 22.1-31.7) and a DCR of 41% at 16 weeks or more. Thirty-one percent of women were treated for 24 weeks or more. Overall, the median PFS for this cohort was 3.5 months (95% CI, 1.8-5.4), and the median OS was 9.8 months (95% CI, 6.8-14.6).

In cohort 2, the ORR was also 14%, the median DOR was 8 weeks (IQR, 7.6-9), and the median DCR was 38%. A total of 28% of patients were treated for more than 24 weeks. The PFS rate at 16 weeks was 38% (95% CI, 21%-55%), the median PFS was 3.5 months (95% CI, 2.9-5.3), and the median OS was 12.4 months (95% CI, 6.4-15.7).

Lastly, for patients with non–clear cell subtypes in cohort 3, the ORR was 21% with an unconfirmed odds ratio of 3%. The median DOR was 41 weeks (IQR, 32.9-49.9), the DCR was 52% at 16 weeks, and 45% were women who were treated for more than 24 weeks. The PFS rate was 54% at 16 weeks (95% CI, 35%-70%), the median PFS was 5.5 months (95% CI, 1.8-8.3), and the median OS was 21.5 months (6.0-not estimable).

Overall, these findings demonstrated clinical activity with ceralasertib alone or in combination with olaparib in rare gynecological cancers. Translational research is ongoing, and investigators are working to identify candidate biomarkers in the near future.

“We have shown that ceralasertib alone and in combination with olaparib has signals of clinical activity in rare gynecologic cancers. In the clear cell carcinoma group— although we did not reach the threshold for response, as required in this trial—other key secondary end points, such as [DOR] and PFS at 16 weeks, are of clinical interest in this signal searching study in rare, aggressive cancers. We did demonstrate activity for the combination in the non–clear cell basket cohort, including carcinosarcoma, providing hypothesis-generating evidence for further investigation,” Banerjee said.

REFERENCE:

Banerjee S, Leary A, Stewart J, et al. ATR inhibitor alone (ceralasertib) or in combination with olaparib in gynaecological cancers with ARID1A loss or no loss - results from the ENGOT/GYN1/NCRI ATARI trial. ESMO Gyanecological Cancers Congress 2023. Abstract 34O.