Title: ATARI: ATr inhibitor in combination with olaparib in gynaecological cancers with ARId1A loss or no loss
Funder: Cancer Research UK

Abstract: Most patients with relapsed gynaecological cancers may initially respond to chemotherapy but eventually the disease becomes resistant to treatment. Ovarian, endometrial (uterine) and cervical carcinomas, which comprise the majority of all gynaecological cancers, are sub-divided into a variety of histological subtypes including clear cell and carcinosarcoma. The clinical outcomes for patients with relapsed disease of clear cell histological subtype and carcinosarcoma are exceptionally poor and effective treatment options are limited. Clear cell, endometrioid carcinomas, carcinosarcomas of ovarian and endometrial origin and cervical carcinomas have been shown to share loss of function mutations in the tumour suppressor gene ARID1A. ARID1A deficiency occurs in a substantial proportion of clear cell and endometrioid cancers (46-57% ovarian clear cell; 26% endometrial clear cell 22-30% ovarian endometrioid; 30-60% endometrial endometrioid). In addition, reports suggest 13- 36% of carcinosarcomas are ARID1A deficient. The clinical significance of ARID1A alterations is not fully known. Currently there is no approved targeted therapy for ARID1A mutant tumours but the reported relatively high frequency of ARID1A mutations or loss of ARID1A expression in gynaecological cancers suggest this may have therapeutic potential. Strategies that incorporate patient selection based on a biomarker have been successful in other cancers including breast and prostate. They are needed to improve the chances of observing sufficient clinical activity in rare gynaecological cancers to warrant further investigation in randomised trials. ARID1A deficiency status is a candidate based on the preclinical work reporting ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. In this international, proof of concept, phase II, parallel cohort trial, assessment of tumour ARID1A expression on tumour specimens will be performed. Patients with relapsed ovarian and endometrial clear cell carcinoma with loss of ARID1A expression will be treated with single agent AZD6738 (Cohort 1A). If AZD6738 monotherapy shows no clinical activity, the combination with olaparib will be tested in this patient group (Cohort 1B). Patients with relapsed ovarian and endometrial clear cell carcinoma with no ARID1A loss will be treated with the combination of olaparib and AZD6738 (Cohort 2). Patients with other cancers of other histological subtypes (endometrioid, carcinosarcoma, cervical), where a relatively high frequency of ARID1A mutation or loss of ARID1A expression is expected, will receive the olaparib and AZD6738 combination (Cohort 3). ATARI will allow pre-clinical observations to be tested clinically and exploration of ARID1A as a predictive biomarker for ATR inhibition in single agent and combination settings with PARP inhibition.

Lay abstract: Most patients with relapsed gynaecological cancers may initially respond to chemotherapy but eventually the disease becomes resistant to treatment. Ovarian, endometrial (uterine) and cervical carcinomas, which comprise the majority of all gynaecological cancers, are sub-divided into a variety of histological subtypes including clear cell and carcinosarcoma. The clinical outcomes for patients with relapsed disease of clear cell histological subtype and carcinosarcoma are exceptionally poor and effective treatment options are limited. Clear cell, endometrioid carcinomas, carcinosarcomas of ovarian and endometrial origin and cervical carcinomas have been shown to share loss of function mutations in the tumour suppressor gene ARID1A. ARID1A deficiency occurs in a substantial proportion of clear cell and endometrioid cancers (46-57% ovarian clear cell; 26% endometrial clear cell 22-30% ovarian endometrioid; 30-60% endometrial endometrioid). In addition, reports suggest 13- 36% of carcinosarcomas are ARID1A deficient. The clinical significance of ARID1A alterations is not fully known. Currently there is no approved targeted therapy for ARID1A mutant tumours but the reported relatively high frequency of ARID1A mutations or loss of ARID1A expression in gynaecological cancers suggest this may have therapeutic potential. Strategies that incorporate patient selection based on a biomarker have been successful in other cancers including breast and prostate. They are needed to improve the chances of observing sufficient clinical activity in rare gynaecological cancers to warrant further investigation in randomised trials. ARID1A deficiency status is a candidate based on the preclinical work reporting ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. In this international, proof of concept, phase II, parallel cohort trial, assessment of tumour ARID1A expression on tumour specimens will be performed. Patients with relapsed ovarian and endometrial clear cell carcinoma with loss of ARID1A expression will be treated with single agent AZD6738 (Cohort 1A). If AZD6738 monotherapy shows no clinical activity, the combination with olaparib will be tested in this patient group (Cohort 1B). Patients with relapsed ovarian and endometrial clear cell carcinoma with no ARID1A loss will be treated with the combination of olaparib and AZD6738 (Cohort 2). Patients with other cancers of other histological subtypes (endometrioid, carcinosarcoma, cervical), where a relatively high frequency of ARID1A mutation or loss of ARID1A expression is expected, will receive the olaparib and AZD6738 combination (Cohort 3). ATARI will allow pre-clinical observations to be tested clinically and exploration of ARID1A as a predictive biomarker for ATR inhibition in single agent and combination settings with PARP inhibition.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS