A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations

Subotheni Thavaneswaran; Maya Kansara; Frank Lin; David Espinoza; John P Grady; Chee Khoon Lee; Mandy L Ballinger; Lucille Sebastian; Theresa Corpuz; Min Ru Qiu; Piyushkumar Mundra; Charles G Bailey; Ulf Schmitz; John Simes; Anthony M Joshua; David M Thomas

doi:10.1038/s41416-023-02311-0

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations

Br J Cancer. 2023 Aug;129(3):475-485. doi: 10.1038/s41416-023-02311-0. Epub 2023 Jun 26.

Authors

Subotheni Thavaneswaran^#^{1

2

3

4}, Maya Kansara^#^{5

6}, Frank Lin^{7

5

6

8}, David Espinoza⁷, John P Grady^{5

6}, Chee Khoon Lee⁷, Mandy L Ballinger^{5

6}, Lucille Sebastian⁷, Theresa Corpuz^{5

6}, Min Ru Qiu^{5

9}, Piyushkumar Mundra^{5

6}, Charles G Bailey^{10

11

12}, Ulf Schmitz^{11

12

13

14}, John Simes⁷, Anthony M Joshua^{15

5

6}, David M Thomas^{15

6

16}

Affiliations

¹ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. [email protected].
² The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia. [email protected].
³ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, Australia. [email protected].
⁴ Garvan Institute of Medical Research, Sydney, NSW, Australia. [email protected].
⁵ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, Australia.
⁶ Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁷ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
⁸ Kinghorn Centre for Clinical Genomics, Sydney, NSW, Australia.
⁹ Department of Anatomical Pathology and Cancer Genetics, SydPath, St Vincent's Hospital, Sydney, NSW, Australia.
¹⁰ Cancer & Gene Regulation Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.
¹¹ Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.
¹² Faculty of Medicine & Health, The University of Sydney, Sydney, NSW, Australia.
¹³ Computational Biomedicine Lab Centenary Institute, The University of Sydney, Camperdown, NSW, 2050, Australia.
¹⁴ Department of Molecular & Cell Biology, College of Public Health, Medical & Vet Sciences, James Cook University, Townsville, QLD, Australia.
¹⁵ The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia.
¹⁶ School of Biomedical Science, University of New South Wales, Sydney, NSW, Australia.

^# Contributed equally.

Abstract

Purpose: To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects.

Patients and methods: In total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on archival tumour tissue and serial bloods.

Results: The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious adverse events related to the study drug(s) in 3 (6%) patients. A higher proportion of CD38 high B cells in the blood and higher CD40 expression in tumour was prognostic of survival.

Conclusions: O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers.

Publication types

Clinical Trial, Phase II
Research Support, Non-U.S. Gov't

MeSH terms

BRCA1 Protein* / genetics
BRCA2 Protein / genetics
Endometrial Neoplasms*
Female
Humans
Phthalazines / adverse effects
Recombinational DNA Repair / genetics

Substances

durvalumab
BRCA1 protein, human
BRCA1 Protein
olaparib
BRCA2 protein, human
BRCA2 Protein
Phthalazines