PARP inhibitors such as olaparib are among the most important cancer drugs of the past decade, but they come with a built-in limitation: they work well only in tumors that already have defects in DNA repair — most famously, BRCA mutations. For the majority of cancers that are “homologous recombination proficient” — roughly 90% of breast cancers and 80% of ovarian cancers — PARP inhibitors offer little benefit.
A study published in the Journal for ImmunoTherapy of Cancer by researchers at the Dartmouth Cancer Center now reveals a potential way around that limitation: telmisartan, an inexpensive, widely used blood pressure medication, dramatically boosts olaparib’s efficacy — even in BRCA-negative tumors — by activating the innate immune system.
“In preclinical models, the combination of telmisartan and olaparib potently controls tumor growth, whereas either drug alone has negligible effect,” said senior author Tyler J. Curiel, a professor of medicine at the Geisel School of Medicine at Dartmouth. “And it does so through a mechanism that is completely distinct from the traditional PARP-inhibitor approach.”
A multi-pronged mechanism
Telmisartan belongs to the angiotensin II receptor blocker (ARB) class of antihypertensives, but the study shows that its cancer-sensitizing effect is not a class property. Among six ARBs tested, only telmisartan depleted tumor PD-L1 and synergized with olaparib in cell lines.
The mechanism has several layers. At the cellular level, telmisartan and olaparib together substantially increase DNA damage — measured as γH2AX, a marker of double-strand breaks — without inducing similar damage in normal cells. This damage is not caused by impairing the tumor’s DNA repair pathways (as traditional PARP-inhibitor sensitization strategies do) but by a different route entirely: the DNA fragments that leak into the cytoplasm activate the cGAS-STING pathway, a central sensor of cytosolic DNA. This triggers production of type I interferons — signaling molecules that orchestrate an immune response.
In mouse models, this interferon response was essential for the combination’s anti-tumor efficacy. When the researchers blocked type I interferon signaling with an antibody or used mice lacking the interferon receptor, the combination therapy lost its effect.
The third layer involves PD-L1, the immune checkpoint protein that many cancers use to evade T-cell attack. Telmisartan depletes PD-L1 in tumor cells, though the Dartmouth team showed that this is not required for the synergy — the combination worked equally well in PD-L1-deficient cells. The increase in PD-L1 observed with the combination is actually a consequence of the interferon response, not a driver of the effect.
BRCA-negative tumors respond
The critical translational finding is that the synergy works in tumors without BRCA mutations or other homologous recombination defects. The researchers tested it in multiple cell lines — ovarian cancer, colorectal carcinoma, triple-negative breast cancer, bladder cancer — and in mouse tumor models. In every case, the combination of telmisartan and olaparib controlled tumor growth significantly better than either drug alone.
“This could expand PARP inhibitor utility to a much larger patient population,” said Clare E. Murray, the study’s first author, who conducted the work as part of her PhD at the UT Health San Antonio Graduate School of Biomedical Sciences.
Two clinical trials are already underway at Dartmouth Hitchcock Medical Center, led by Curiel. A Phase 1 trial (NCT06168487) is testing telmisartan with olaparib and other standard-of-care drugs in men with metastatic castration-resistant prostate cancer; the first participant has shown what the investigators describe as an “exceptional response.” A Phase 2 trial (NCT06815497) is testing telmisartan with chemotherapy in women with platinum-resistant ovarian cancer.
Both trials are early-stage, single-center, open-label studies — the typical caution applies. The preclinical studies were conducted entirely in cell lines and mouse models, and the precise molecular target of telmisartan’s non-ARB moiety — the part of the molecule responsible for the synergy — has not been identified. The researchers note that they “did not exclude additional mechanisms” for the observed effect.
Nevertheless, telmisartan’s advantages for drug repurposing are clear: it is approved by the US Food and Drug Administration, available as a generic, safe even in people with normal blood pressure, and taken as a once-daily pill. If the clinical trials confirm the preclinical findings, the combination could reach patients far faster than a novel drug could.
Source: Murray, C.E., Ontiveros, C.O., Wentworth, J. et al. “Telmisartan increases olaparib efficacy in homologous recombination proficient tumors by augmenting type I interferon production.” Journal for ImmunoTherapy of Cancer 14(3), e012426 (2026). DOI: 10.1136/jitc-2025-012426