The next hope for synthetic lethality still revolves around PARP, the only target so far validated by both clinic and market.

The PARP family comprises 17 members. Most first-generation PARP inhibitors lack subtype selectivity and exert broad-spectrum inhibition on PARP1, PARP2, and other family members. As clinical use progressed, their limitations gradually emerged: adverse events including hematological toxicity, gastrointestinal reactions, and renal injury restricted long-term administration and combination therapy.

Dr. Cai Suixiong, CEO of Impact Therapeutics, pointed out that the anti-tumor activity of PARP inhibitors mainly derives from PARP1 inhibition, whereas hematological toxicity is highly associated with PARP2 inhibition. This non-selective “bundling” mechanism makes it difficult to decouple efficacy and safety. Therefore, developing highly selective PARP1 inhibitors that maximally avoid PARP2 has become the core logic of next-generation R&D.

“PARP1 and PARP2 differ in their enzymatic domains, providing a structural basis for designing highly selective molecules,” Dr. Cai noted.

According to incomplete statistics, about a dozen PARP1-selective inhibitors have entered clinical development.

The fastest progress is AstraZeneca’s AZD5305, a novel PARP1 “trap-type” inhibitor that not only suppresses catalytic activity but also efficiently traps PARP1 at DNA damage sites, amplifying and prolonging DNA damage signaling. Previously disclosed data show that its selectivity for PARP1 is approximately 500-fold over PARP2, and it has advanced to Phase III clinical trials.

AstraZeneca first shared human clinical data for AZD5305 at the AACR conference in 2022, after which the PARP1 inhibitor field entered a period of intensive licensing deals.

• September 2022: Merck KGaA in-licensed NMS-03305293 from NMS Group.
• 2023 saw intensified transactions:
  • May: Gilead acquired XinThera, gaining its preclinical PARP1 inhibitor assets.
  • June: Impact Therapeutics granted Eikon global rights (excluding Greater China) to IMP1734 and IMP1707.
  • October: Merck KGaA struck again, in-licensing HRS-1167 from Hengrui Medicine with a $160 million upfront payment.

Currently, the landscape of the PARP1 inhibitor field is largely clear: besides frontrunner AZD5305, Hengrui’s HRS-1167 and Impact’s IMP1734 are among the most advanced.

Data show that IMP1734 has >648-fold selectivity for PARP1 over PARP2, ranking among the top globally in disclosed data. Its clinical development focuses on major PARP-sensitive tumors including breast, prostate, and ovarian cancers. Global Phase I/II trials are ongoing to evaluate monotherapy efficacy and combinations with abiraterone and paclitaxel, with data expected in 2026.

Beyond selective inhibition, some PARP1 inhibitors possess strong blood-brain barrier (BBB) penetration, creating differentiated competitive advantages.

For example, AstraZeneca’s AZD9574 features both “high PARP1 selectivity + BBB penetration,” showing greater potential for brain metastases or primary gliomas (e.g., IDH-mutant gliomas).

Impact Therapeutics’ IMP1707 shows >800-fold PARP1 selectivity over PARP2, mechanistically avoiding hematological toxicity caused by PARP2 inhibition in traditional PARP inhibitors, while achieving potent BBB penetration. Non-clinical studies demonstrated complete tumor regression in brain cancer models at a minimum effective dose of 0.2 mg/kg.

Effective treatments for brain metastases and brain tumors remain extremely limited. If such brain-penetrating PARP1 inhibitors validate intracranial activity in the clinic, they could fill a treatment gap unreachable by conventional PARP inhibitors.

If second-generation PARP inhibitors “inwardly” solve tolerability issues, their greater strategic value lies in “outwardly” unlocking the potential of combination therapy — precisely aligning with the core paradigm shift in current oncology drugs.

The era of single-agent dominance in cancer treatment is over. Major therapeutic breakthroughs in recent years — whether chemotherapy, targeted therapy, or immunotherapy — have mostly come from elegant combination strategies.

The most typical example is PD-1/PD-L1 inhibitors: their rise to a hundred-billion-dollar market empire largely stems from their ability to form highly effective combinations with chemotherapy, targeted agents, and even other immunotherapies, expanding across dozens of indications.

First-generation PARP inhibitors were severely restricted in combination use by hematological toxicity; many potentially powerful regimens were too toxic to be fully explored clinically. Safety improvements in second-generation PARP inhibitors are breaking this constraint.

Combination therapy also means expanded market space. Patients with DDR pathway defects such as BRCA mutations are a limited population, but combination strategies can extend PARP inhibitors to a broader range of solid tumors.

AZD5305’s Phase III clinical layout clearly reflects this logic:

• Three ongoing Phase III trials, all in combination:
  • Combined with camizestrant for HR+/HER2−, BRCA/PALB2-mutant advanced breast cancer;
  • Combined with NHA for metastatic castration-sensitive prostate cancer;
  • Combined with ADT ± abiraterone for high-risk BRCA-mutant prostate cancer.

Combination directions for PARP inhibitors continue to expand:

• With PD-1 inhibitors: leveraging genomic instability from DDR defects to increase tumor immunogenicity and reverse the immunosuppressive microenvironment;
• With ADCs: enhancing payload cytotoxicity by inhibiting DNA repair.

“In the future, the direction will likely be combinations among several different synthetic lethality drugs, or between synthetic lethality drugs and other modalities (targeted, immune, ADC),” Dr. Cai predicted. “Second-generation PARP inhibitors with better safety will play a more flexible and central role in this combination ecosystem.”

In fact, the combination wave has swept the entire synthetic lethality sector. For emerging targets beyond PARP, single-agent efficacy development is exceptionally challenging.

“Identifying a specific patient population dependent on a single target and achieving impressive single-agent efficacy is highly challenging,” Dr. Cai noted. Thus, combination therapy has become almost the only path forward for these targets.

The path is not without setbacks. Recently, AstraZeneca’s ATR inhibitor ceralasertib combined with Imfinzi failed to meet the primary endpoint in a Phase III trial for non-small cell lung cancer, sparking industry debate.

Dr. Cai advocates a rational view: “It is hard to attribute this failure to the synthetic lethality mechanism itself.” He pointed out that large-scale early attempts to combine PARP inhibitors with PD-1/PD-L1 inhibitors “mostly failed,” as the underlying hypothesis — DNA damage inducing neoantigen expression and enhancing immune sensitivity — had weak preclinical mechanistic support. “This is a failure for an ATR inhibitor, but it is unfair to blame synthetic lethality.”

ATR is still regarded as one of the most promising next-generation targets in synthetic lethality after PARP.

Impact Therapeutics has positioned its ATR inhibitor as a core combination partner for senaparib (its PARP1/2 inhibitor), focusing on patients resistant to PARP inhibitors. Related combination trials have been initiated. The “PARPi + ATRi” regimen aims to deliver a dual hit on DNA repair and extend the lifecycle of core products.

Indeed, new promising combination effects are emerging for ATR inhibitors, such as with ADCs.

Many ADC payloads are DNA-damaging agents (e.g., topoisomerase I inhibitors). Blocking DNA repair pathways with PARP inhibitors leads to massive DNA damage accumulation, significantly amplifying ADC cytotoxicity. Artios’ ART0380 combined with low-dose irinotecan has shown positive signals in Phase I/IIa trials.

As technical routes evolve, so do capital narratives.

The development of synthetic lethality can be roughly divided into three phases:

1. PARP-only Era 1.0: The BRCA-PARP golden pair completed proof-of-concept and commercialization.
2. Target Proliferation Era: A surge of new potential synthetic lethality targets — ATR, Wee1, Polθ, USP1, etc. — sparked an investment boom.
3. Current Phase: Calm Reflection & Model Exploration: After these new targets entered deep clinical validation, the industry is re-evaluating technical and commercial pathways.

Capital no longer readily buys into novel target stories; instead, it favors companies with clearer competitive barriers and iteration capabilities in the post-PARP era.

In December 2025, Sanctity Biologics, a biotech focused on DNA damage response (DDR) innovative drugs, announced over ¥100 million Series A financing. Its pipeline centers on combination therapy, overcoming resistance, and expanding new indications. Its core asset SYN818 is a highly selective Polθ inhibitor that precisely disrupts the DNA damage repair mechanism in tumor cells and selectively induces cancer cell death.

In November of the same year, Artios completed Series D financing, with investors including Andera Partners, Janus Henderson, RA Capital Management, and SV Health Investors. Founded in 2016 and focused on DDR pipelines, the company also emphasizes a platform-based pipeline and combination strategy.

As one of China’s most comprehensive players in synthetic lethality, Impact Therapeutics has submitted a Hong Kong IPO application, aiming to become the “Synthetic Lethality First Stock” on the HKEX.

“Platform capability” is replacing “single target” as the new yardstick for measuring long-term company value. Dr. Cai stated that platformization is an industry trend.

“If you only have one or two synthetic lethality molecules, you will be constrained everywhere and need constant external partnerships to explore combinations. But with an R&D platform encompassing multiple target molecules, you can freely combine them internally to form a strong pipeline matrix, while gaining greater initiative and flexibility in external collaborations.”

Dr. Cai revealed that Impact Therapeutics is not limited to monotherapy development; its real focus is exploring combinations of synthetic lethality with ADCs, RDCs, and immunotherapies. For instance, leveraging its highly potent synthetic lethality library and technology platform, the company is advancing dual-payload ADCs designed based on synthetic lethality principles. In his view, this technical route has clear entry barriers that are difficult for other players to replicate in the short term.

More than a decade ago, synthetic lethality succeeded with a single target, forging a complete chain from theory to marketed drug.

A decade later, the industry has realized that the hardest part is not finding the next PARP, but enabling more targets to find their ecological niche within a network of combination therapies.

The narrative of searching for “the next hope” remains, but more companies are no longer fixated on blockbuster single agents. Instead, they are thinking about how to embed synthetic lethality logic into broader therapeutic combinations. This may be the true evolutionary direction of the field in the post-PARP era.