175: Drug-Drug Interaction (DDI) Study of the PROteolysis Targeting Chimera (PROTAC) Androgen Receptor (AR) Degrader Bavdegalutamide in Combination With the CYP3A4 Inhibitor Itraconazole in Healthy Volunteers

Statement of Purpose: Bavdegalutamide (ARV-110) is a potent, selective, orally bioavailable, PROTAC small molecule that induces the degradation of the AR and is being developed for the treatment of prostate cancer. Bavdegalutamide 420 mg once-daily (QD) dose has demonstrated an acceptable safety profile in ongoing clinical studies in men with prostate cancer. In vitro assessment indicated cytochrome P450 (CYP) 3A4 as the principal isoform contributing to CYP-based metabolism for bavdegalutamide. Itraconazole, as the perpetrator drug, is a synthetic triazole antifungal agent and a strong inhibitor of CYP3A4. Here, we describe a DDI study that evaluated the impact of multiple dosing of itraconazole on the pharmacokinetics (PK) of a single dose of bavdegalutamide in healthy male participants. Safety also was evaluated.

Description of Methods & Materials: This was a Phase 1, open-label, 2-treatment, fixed sequence, crossover study in healthy male volunteers. During treatment A, participants received a single oral dose of bavdegalutamide 280 mg on Day 1 in a fed state. During treatment B, participants received itraconazole 200 mg oral solution twice on Day 1 and QD thereafter until Day 16; on Day 4 participants also received a single oral dose of bavdegalutamide 280 mg in a fed state. There was a 28-day washout phase between bavdegalutamide doses. A dose of bavdegalutamide 280 mg was considered adequate to establish the potential for DDI with a CYP3A inhibitor and to mitigate the risk of expected increased bavdegalutamide exposure. PK samples for bavdegalutamide were collected at predose and at selected times through 312 hours post-bavdegalutamide dose. Primary endpoints were area under the curve from the time of dosing to the time of the last measurable concentration (AUC_last) and maximum plasma concentration (C_max) of bavdegalutamide. Secondary endpoints included additional PK parameters and treatment-emergent adverse events (TEAEs).

Data & Results: A total of 20 participants were included in the safety and PK analysis populations; data for the 17 participants who completed both treatments were used in the PK analysis. Bavdegalutamide co-administered with itraconazole resulted in approximately 2-fold higher extent of exposure and 1.5-fold higher peak exposure compared with bavdegalutamide alone (Table). The presence of itraconazole prolonged mean bavdegalutamide elimination half-life (by ≈40 hours; 134.5 hours vs 95.1 hours), delayed median time to C_max (from 6.0 to 8.0 hours), and decreased apparent total body clearance and volume of distribution (by ≈2-fold and ≈1.4-fold, respectively). TEAEs occurred in 10 (50%) participants and were all grade 1/2. The most common TEAEs experienced by 3 (15%) participants each were fatigue and headache. All of the fatigue events and 1 headache event were considered probably related to bavdegalutamide.

Interpretation, Conclusion or Significance: Co-administration of bavdegalutamide with the CYP3A4 inhibitor itraconazole markedly increased the peak concentration and extent of systemic exposure of bavdegalutamide, suggesting that bavdegalutamide should not be co-administered with strong CYP3A4 inhibitors in clinical studies. A single oral dose of bavdegalutamide 280 mg alone or in combination with itraconazole was generally well tolerated by healthy male volunteers.

Disclosures: All authors are employees of Arvinas Operations Inc.