LB-005 - TALAZOPARIB FORMULATION BRIDGING IN CANCER PATIENTS-CHALLENGES AND THE CRITICAL ROLE OF MIDD IN APPROVAL DESPITE FAILED BIOEQUIVALENCE

C. Guo¹, D. Wang², X. Gao³, Y. Wang⁴, Y. Yu⁵, A. Plotka³, M. Elmeliegy³, H. Shi³, S. Johnson³, L. DeAnnuntis³, J. Hoffman³; ¹Pfizer, CA, Santa Barbara, ²Pfizer, san diego, CA, san diego, ³Pfizer, san diego, san diego, ⁴Gilead, san diego, CA, san diego, ⁵Genentech, san diego, san diego.

Background: Talazoparib is a PARP inhibitor approved for the treatment of breast and prostate cancer. A new SGC formulation was developed post approval for commercial use which required a bioequivalence (BE) and food effect (FE) study to bridge the SGC with the initial commercial HC formulation. Study execution and meeting BE criteria are challenging, due to high variability in Cmax, potentially higher Cmax for SGC based on dissolution data and the need to run the BE/FE assessment at steady state in cancer patients. This work showcased how MIDD facilitated an efficient/feasible study design and supported the approval of SGC formulation.

Methods: The clinical relevance of AUC and Cmax on safety was evaluated using semi-mechanistic PK/PD models for hematological endpoints (anemia, thrombocytopenia and neutropenia) which are the main side effects of talazoparib. Population PK model was used to evaluate the shortest duration possible for BE/FE assessment to minimize the impact of patient dropout on sample size for enrollment. Various designs were considered (Fig 1). BE was assessed based on 90% confidence intervals for the geometric mean ratio of the test/reference for AUC and Cmax and safety data were collected.

Results: PK/PD simulation showed that up to 52% increase of Cmax did not worsen hematological side effects, when AUC remained the same. This supported a BE study powered for AUC equivalence only. PK simulation showed that following 28-day treatment in the first period, 14 days in subsequent periods is sufficient for steady-state BE/FE assessments. These MIDD findings supported the study design in Fig 1A which had reduced sample size, making the study in cancer patients feasible. Study results showed AUC met the BE criteria while Cmax was 37% higher for the SGC relative to the HC, which was deemed not clinically significant based on the PK/PD model. FE on SGC formulation was consistent with FE on HC formulation reported previously. Safety profile of the two formulations was similar with no new safety signals identified.

Conclusion: The totality of data (AUC equivalence, lack of impact of Cmax on safety endpoints and observed safety data) supported bridging of the SGC formulation with the initial commercial HC formulation even though Cmax failed to meet BE criteria. MIDD was critical in study design optimization and supported the approval of the SGC formulation.