PII-115 - EVALUATION OF THE EFFECT OF VEPDEGESTRANT, A PROTEOLYSIS TARGETING CHIMERA (PROTAC) ESTROGEN RECEPTOR (ER) DEGRADER, ON ROSUVASTATIN PHARMACOKINETICS (PK) IN HEALTHY ADULT PARTICIPANTS.

L. Zhou¹, J. Winton², K. Matschke³, K. Doyle⁴, K. Lee², Y. Zhang⁵, W. Tan¹; ¹Pfizer, Inc., San Diego, CA, USA, ²Pfizer, Inc., Groton, CT, USA, ³Pfizer, Inc., Collegeville, PA, USA, ⁴Pfizer, Inc., New Haven, CT, USA, ⁵Arvinas Operations, Inc., New Haven, CT, USA.

Background: Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and showed encouraging clinical activity in patients with ER+/human epidermal growth factor receptor 2-negative breast cancer in a first-in-human phase 1/2 study (NCT04072952). The objective of this study was to evaluate the impact of vepdegestrant on the PK of the breast cancer resistance protein (BCRP) substrate rosuvastatin in healthy adult participants (NCT05652660).

Methods: This was a phase 1, open-label, 2-period, fixed-sequence study in healthy male and female adults; female participants had to be of non-childbearing potential. In period 1, a single oral dose of rosuvastatin 10 mg was administered in the fed state. In period 2, a single oral dose of rosuvastatin 10 mg was administered about 90 minutes following a single oral dose of vepdegestrant 200 mg in the fed state. Serial blood PK samples were collected up to 72 hours post-rosuvastatin dose.

Results: A total of 12 participants were enrolled and treated in this study. Co-administration of rosuvastatin with vepdegestrant increased the maximum plasma concentration (C_max) of rosuvastatin by 21% and the area under the curve from time 0 to time of the last quantifiable concentration (AUC_last) of rosuvastatin by 11%. The ratios of the adjusted geometric means (90% CI) for rosuvastatin C_max and AUC_last were 120.50% (104.77%–138.59%) and 110.56% (103.53%–118.06%), respectively, following rosuvastatin administration with vepdegestrant (test) compared with administration alone (reference). Adverse events (AEs) occurred in 1 (8.3%) participant after rosuvastatin treatment and 3 (25.0%) participants after rosuvastatin and vepdegestrant combination treatment. All AEs were mild, no serious or severe AEs occurred, and no discontinuations due to AEs were reported. Participants reported treatment-related AEs of dizziness and headache (1 [8.3%] each) after co-administration of rosuvastatin with vepdegestrant.

Conclusion: Co-administration of vepdegestrant had a minor effect on rosuvastatin exposure, suggesting vepdegestrant to be a weak BCRP inhibitor; dose reductions of BCRP substrate drugs are not warranted in patients taking vepdegestrant. Study treatments were well tolerated in healthy adult participants.