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

Sep 24, 2026

A signal-seeking Phase II clinical trial evaluates PARP plus PD-L1 inhibition with olaparib and durvalumab in patients with advanced solid tumors carrying homologous recombination repair (HRR) defects, including predominantly rare cancers. Forty-eight patients received the combination, with cohorts defined by BRCA1/2 alterations versus other selected HRR alterations. The primary endpoint is progression-free survival at 6 months, with post hoc exploratory analyses using archival tumor tissue and serial blood samples. Results report a 35–38% PFS6 rate and durable objective tumor responses. The combination shows no new toxicity signals and identifies potential prognostic immune markers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Purpose

Patients and methods

Results

Progression-free survival and objective tumor responses

Conclusions

Safety and prognostic markers

British Journal of Cancer [www.nature.com/bjc](www.nature.com/bjc) ARTICLE OPEN A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations Subotheni Thavaneswaran 1,2,3,4,13 ✉, Maya Kansara3,4,13, Frank Lin1,3,4,5, David Espinoza1, John P. Grady 3,4, Chee Khoon Lee1, Mandy L. Ballinger3,4, Lucille Sebastian 1, Theresa Corpuz3,4, Min Ru Qiu3,6, Piyushkumar Mundra3,4, Charles G. Bailey7,8,9, Ulf Schmitz 8,9,10,11, John Simes 1, Anthony M. Joshua 2,3,4 and David M. Thomas2,4,12 © The Author(s) 2023 | | 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 singlearm 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. | | | | | British Journal of Cancer (2023) 129:475–485; [https://doi.org/10.1038/s41416-023-02311-0](https://doi.org/10.1038/s41416-023-02311-0) | | | | | | BACKGROUND Homologous recombination repair (HRR) is comprised of interwoven pathways that function in the repair of DNA doublestranded breaks and interstrand crosslinks [1] . An inability to repair complex DNA damage and resolve DNA replication strain results in genomic instability and promotes cancer development [1] . BRCA1 and 2 are the best-characterised HRR genes and predispose to breast and ovarian cancer [2, 3] . Several additional genes have been implicated in this repair pathway and many studies have characterised the exploitation of these inherent defects for therapeutic opportunities [4–6] . The use of poly-ADP ribose polymerase (PARP) inhibitors has synthetically lethal activity in the presence of non-functional HRR. Olaparib monotherapy has yielded a prolonged progression-free survival in patients with relapsed platinum-sensitive high-grade serous ovarian cancer, particularly in the presence of germline or somatic BRCA1/2 alteration [7–10] . Similarly, improved outcomes have been observed with olaparib across a range of cancer histotypes harbouring BRCA1/2, or other HRR gene alterations [5, 11–15] . Generally, patients with BRCA mutations derived greater beneﬁts from olaparib treatment compared with other HRR gene alterations [16] . There is signiﬁcant interest in the immunological consequences of DNA damage. Preclinical data suggest that DNA damage detected by the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway triggers a proinﬂammatory cascade of cytokines [17] . Preclinically, PARP inhibition elicits a potent antitumour immune response through activation of the STING pathway in both BRCA1-deﬁcient tumour cells and dendritic cells, possibly indicating an association between innat

FAQs

What treatment combination is studied in this Phase 2 trial?

The study evaluates olaparib (PARP inhibition) plus durvalumab (PD-L1 inhibition) in advanced solid cancers with HRR gene alterations.

How were patients grouped for analysis?

Patients were treated with olaparib plus durvalumab and analyzed in two cohorts: those with BRCA1/2 alterations (group 1) and those with other selected HRR alterations (group 2).

What were the main efficacy and safety outcomes?

Progression-free survival at 6 months was reported as 35% (group 1) and 38% (group 2), alongside durable objective tumor responses. The combination was considered safe, with serious adverse events related to the study drugs occurring in 3 (6%) patients and no new toxicity concerns in the conclusions.

Sep 24, 2026

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