Zentalis Pharmaceuticals (ZNTL) Study Update summary

Clinical and Efficacy Highlights

• Azenosertib achieved consistent objective response rates above 30%, with DENALI Part 1b showing a 34.9% ORR and median duration of response (mDOR) of approximately 5.5 months in heavily pretreated Cyclin E1+ platinum-resistant ovarian cancer (PROC) patients across multiple studies at doses of 300mg or higher on a five days on, two days off schedule.

• Efficacy was particularly notable in PARP inhibitor-resistant and heavily pretreated subgroups, with non-Cyclin E1+ patients showing much lower ORR (~6%).

• Responses were durable, with mDOR trending upwards as more patients remain on therapy.

• Azenosertib is also being explored in other Cyclin E1+ tumor types, including breast, endometrial, and bladder cancers.

• Combination studies in BRAF-mutant colorectal cancer showed 35% response in BRAFi-naïve patients, but will not advance due to resource prioritization.

Safety and Tolerability

• Azenosertib demonstrated a well-characterized, manageable safety profile at both 300mg and 400mg 5:2 doses, with most adverse events being low grade and low rates of grade 3+ hematologic toxicities and treatment discontinuations.

• Serious hematologic and GI toxicities were infrequent, and mitigation strategies reduced higher-grade events.

• Grade 5 events occurred in a small percentage of patients, mainly in heavily pretreated populations, and were attributed to multifactorial causes.

• Safety profile was consistent across studies and favorable compared to standard chemotherapy.

• Additional mitigation strategies are planned to further reduce risk and improve duration on therapy.

Biomarker and Patient Selection

• Cyclin E1 overexpression, present in about 50% of PROC patients, was established as a predictive biomarker for response to azenosertib.

• The companion immunohistochemistry assay enables rapid identification of eligible patients, capturing both DNA amplification and protein overexpression.

• Cyclin E1 positive patients have poorer outcomes with standard chemotherapy, highlighting the unmet need addressed by azenosertib.

• The biomarker-driven approach is expected to enhance the risk-benefit profile and support regulatory strategy.

• The cyclin E1 assay cutoff is designed to maximize response, though a small subset with DNA amplification but not overexpression may be missed.