Abstract

Background: The success of novel therapies as they progress in later phases of clinical development requires accurate benchmarking of the benefit provided by the standard of care (SOC) at the time of clinical study completion. Information collected from published investigational studies or retrospective registries can be outdated or may not reflect the most current SOC. Furthermore, the development of novel agents, especially for patients on later lines of treatment, may be restricted to select populations, not previously characterized in the literature, perhaps defined by criteria such as a novel biomarker (e.g. Cyclin E1 positive tumors) or narrow indication sub-types (e.g., platinum resistant ovarian cancer with less than N prior therapy lines). Here, we demonstrate how the analysis of Real-World Data (RWD), as well as screening data — collected in the context of recent early phase clinical studies — is guiding development of the WEE1 inhibitor azenosertib in Cyclin E1 positive high grade serous ovarian cancer (HGSOC).

Methods: The records of medications and lines of therapy were curated from Tempus Lens (TLOv) or Zentalis Retrospective Study of Early Treatment (ReSET) cohorts. Outcomes such as best response, progression free survival and treatment free survival were evaluated for patient subsets defined by treatment history or Cyclin E1 expression status from RNA sequencing (for TLOv) or protein immunohistochemistry (IHC for ReSET) after benchmarking RNA-based classification using independent HGSOC tissues (N=92).

Results: Compared to IHC, RNA-based Cyclin E1 classification was > 70% accurate, with higher rates of False Negative than False Positives, providing an acceptable surrogate to stratify patients in the TLOv cohort. The treatment regimens used in early lines were consistent between TLOv and ReSET cohorts and reflected current SOC, including partial use of PARPi in 1L maintenance and a preference for doxorubicin-based regimens in 2L for platinum-resistant patients. The data confirmed previous observations that BRCA-mutated patients had better prognosis, likely due to PARPi treatment eligibility after 1L. Patients with Cyclin E1 positive tumors were observed in both platinum-resistant and platinum-sensitive settings, with a higher prevalence in platinum-resistant setting. Patients with Cyclin E1 positive tumors had worse outcomes in 1L, or with selected treatment regimens in subsequent lines, highlighting their consistent unmet need throughout the entire treatment journey.

Conclusions: RWD represents a reliable and up-to-date source of treatment and outcomes information for HGSOC patients. Clean identification of lines and intent of treatment as well as availability of direct or surrogate Cyclin E1 expression status were key to highlighting the unmet need of patients with Cyclin E1 positive tumors, informing azenosertib’s development.

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