Limitations of First-Generation PARP Inhibitors and the Challenge of Overcoming Resistance

First-generation poly ADP-ribose polymerase (PARP) inhibitors have been at the forefront of ovarian and breast cancer treatment by leveraging DNA repair defects in cancer cells to induce synthetic lethality. AstraZeneca's Lynparza, with an active ingredient of olaparib, recorded global sales of approximately $3 billion in 2025, dominating the market. However, with long-term administration, mechanisms of drug resistance, such as BRCA reversion, where cancer cells restore their DNA repair function, are frequently reported. Furthermore, due to the non-selective inhibition of PARP1 and PARP2, serious myelosuppression side effects, such as anemia and neutropenia, are observed, which has become a bottleneck factor increasing the rate of treatment discontinuation in patients.

Strengthening of Companion Diagnostic Criteria by Regulatory Agencies and Trend of Reduced Indications

As the importance of patient selection in clinical practice is highlighted, regulatory agencies such as the U.S. Food and Drug Administration (FDA) are gradually narrowing the scope of companion diagnostic criteria. For example, GSK's Zejula, with an active ingredient of niraparib, had its indication for first-line ovarian cancer maintenance therapy narrowed to HRD-positive patients by the FDA in June 2025. This demonstrates the urgent need for precise biomarker-based personalized treatment, as existing HRD tests do not accurately reflect the real-time tumor status. Pfizer's Talzenna, with an active ingredient of talazoparib, also showed limited efficacy in prostate cancer clinical trials in patients other than those with BRCA mutations, leaving the challenge of further targeting.

Second-Generation PARP1-Selective Inhibitor Saruparib Enters Phase 3 Clinical Trial

To overcome the existing toxicity side effects, global pharmaceutical companies are accelerating the commercialization of second-generation PARP1-selective inhibitors with reduced side effects. AstraZeneca has initiated a Phase 3 clinical trial of saruparib (development code AZD5305), which has lower myelotoxicity and is easy to use in combination therapy, in order to gain a leading position in the market. Several global clinical trials, including EvoPAR-Breast01 (NCT06380751, initiated in August 2024) for breast cancer and EvoPAR-Prostate02 (NCT06952803, initiated in August 2025) for prostate cancer, are progressing smoothly. The highly selective second-generation drug is expected to shake up the market by maximizing the therapeutic efficacy as a single agent and enabling safe combination with other anticancer drugs.

Exploring Synergistic Effects with Next-Generation DNA Damage Response Target Therapies

To circumvent the resistance limitations of first-generation therapies, the industry is exploring multifaceted blockade of the DNA damage response (DDR) pathway. For example, ART6043, a DNA polymerase theta (Polθ) inhibitor developed by Artios Pharma, received Fast Track designation from the FDA in February 2026 for use in combination with Lynparza and has entered Phase 2 POLKA clinical trial (NCT05898399). In addition, Roche, which returned the rights to ATR inhibitor camonsertib from Repare Therapeutics, is also continuing its independent development, which is attracting attention. These next-generation combination therapies are expected to provide a powerful alternative for cancer patients with resistance, stimulating long-term research and development investment and demand for skilled personnel.