Beyond PARP – What’s Next For DNA Damage Response-targeted Therapies?

The clinical success of poly ADP ribose polymerase (PARP) inhibitors established the DNA damage response (DDR) as a major therapeutic target in oncology and validated the concept of synthetic lethality. With resistance to first-generation therapies increasingly observed in clinical practice, and foundational patents approaching expiry, the field is expanding beyond PARP inhibition toward new therapeutic strategies. This insight explores emerging DDR-targeted therapies beyond PARP inhibition and the role of intellectual property (IP) in supporting innovation in this increasingly competitive field.

From PARP inhibitors to next-generation DDR targets

DNA damage and genomic instability are key drivers of cancer development and progression, making the DNA damage response (DDR) an important therapeutic target in oncology. To maintain genomic integrity, cells rely on the DDR, a network of pathways responsible for detecting and repairing DNA lesions. Many cancers harbour defects in specific DDR pathways, making them more dependent on their remaining repair mechanisms for survival. DDR-targeted therapies aim to exploit these tumour-specific repair vulnerabilities. In contrast to conventional genotoxic chemotherapies, which induce widespread DNA damage in both healthy and tumour cells, DDR-targeted approaches aim to improve selectivity and reduce off-target toxicity.

The clinical success of PARP inhibitors, such as olaparib, provided the first major validation of this approach. In tumours carrying BRCA1 or BRCA2 mutations, PARP inhibition leads to the accumulation of DNA damage that these cancer cells cannot repair. This results in selective tumour cell death, while largely sparing normal cells – a mechanism known as synthetic lethality. However, resistance to first-generation agents is increasingly observed in patients, highlighting the need for continued innovation.

Emerging DDR-targeted therapies are expanding beyond PARP inhibition to exploit additional vulnerabilities in DNA repair and cell-cycle regulation. Key targets include ATR, ATM, WEE1, DNA-PK, Chk1 and polymerase theta, which regulate cellular responses to replication stress and DNA damage. Inhibition of these pathways can disrupt DNA repair or abrogate cell-cycle checkpoints, forcing tumour cells to divide with unrepaired DNA. This results in mitotic catastrophe or cell death.

As research into these targets accelerates, the DDR landscape is becoming increasingly competitive. Securing IP protection requires establishing novelty and inventive step – a potentially high hurdle in crowded areas with overlapping target classes. Freedom-to-operate (FTO) considerations also remain essential for innovators seeking to develop and commercialise DDR-targeted therapies.

AI-enabled approaches in DDR drug discovery and IP

To date, PARP inhibitors remain the only DDR-targeted therapies with broad regulatory approval in oncology, while other DDR inhibitors are still in clinical development.

Artificial intelligence (AI) and machine learning, often combined with CRISPR-based functional genomic screening, are increasingly used in DDR drug discovery. These approaches support the identification of DNA repair vulnerabilities, prediction of synthetic lethal interactions, prioritisation of therapeutic targets and development of biomarker strategies for patient stratification. By integrating large-scale genomic and phenotypic datasets, AI methods can help capture tumour heterogeneity and identify patient subgroups most likely to respond to specific DDR-targeted therapies.

From an IP perspective, AI-assisted inventions in DDR drug discovery may be patentable under UK and European law, provided they demonstrate a technical contribution and are directed to a technical purpose.

AI-enabled DDR research and drug discovery can generate several categories of potentially patentable inventions including:

• Novel small molecules targeting DDR proteins identified or prioritised using AI-assisted screening approaches.
• Computational methods (“discovery engines”): AI-driven workflows that integrate proprietary models and curated biological datasets to identify DDR vulnerabilities or predict synthetic lethal interactions.
• Precision diagnostics: AI-driven biomarker methods for matching patient groups with the most appropriate DDR therapies

These AI-enabled approaches raise key IP considerations, including patent eligibility, inventive step and sufficiency of disclosure. Careful early-stage IP strategy and claim drafting are therefore critical to secure meaningful protection.

Combination therapy patents for DDR-targeted therapies

Combination approaches are an increasingly important area of DDR research, driven by the need to overcome resistance to monotherapies and expand clinical benefit across genetically defined tumour populations. DDR inhibitors are being explored in combination with radiopharmaceutical agents and immunotherapies, among other approaches.

In combination with radiopharmaceutical and radioligand therapies, which deliver localised DNA damage specifically to tumour cells, DDR inhibition can enhance therapeutic efficacy. By impairing tumour DNA repair, DDR inhibitors amplify therapy-induced double-strand DNA breaks, increasing tumour cell death while maintaining the specificity of treatment to minimize systemic toxicity.

DDR inhibitors are also being evaluated in combination with immune checkpoint inhibitors such as anti-PD-1/PD-L1 therapies. By impairing DNA repair, these agents can increase the accumulation of cytosolic DNA fragments in tumour cells, activating innate immune signalling pathways. This may enhance tumour immunogenicity and convert “cold” tumours into more immunologically active “hot” tumours..

From a commercial and IP perspective, DDR combination therapies may offer opportunities to extend protection for existing drugs and potentially expand the treatable patient population.

In the UK and Europe, patent protection may be obtained through second medical use claims, including for:

• Specific patient subgroups (e.g. genetically defined tumours)
• Specific combination regimens
• Optimised dosing schedules
• Co-administration with other anticancer agents e.g. immunotherapy or radiotherapy

Securing patent protection for combination therapies requires proving an “inventive step”, i.e. that the combination was non-obvious or provided unexpected improved effects. In some cases, synergy can be used in support of inventive step. For example the combination may deliver a clinical bonus that is greater than the sum of its parts, such as enhanced immune activation, radiosensitisation, or superior tumour-specific efficacy. Once again, careful drafting of the patent application will be critical. The European Patent Office, for example, requires the technical effect relied on for inventive step to be encompassed by the technical teaching of the original application.

Our firm can assist clients in identifying patentable combination strategies, structuring robust second medical use claims, and advising on freedom-to-operate consideration in this increasingly complex and competitive landscape.

J A Kemp LLP acts for clients in the USA, Europe and globally, advising on UK and European patent practice and representing them before the European Patent Office, UKIPO and Unified Patent Court. We have in-depth expertise in a wide range of technologies, including Biotech and Life Sciences, Pharmaceuticals, Software and IT, Chemistry, Electronics and Engineering and many others. See our website to find out more.

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