Abstract P3-11-04: Phase I/II trial of palbociclib in combination with bicalutamide for the treatment of androgen receptor (AR)+ metastatic breast cancer (MBC)
Authors: Gucalp A , Edelweiss M , Patil S , Gounder MM , Feigin KN , Corben A , Arumov A , Traina TA 
Published: February 2018

Abstract
Background: The androgen-signaling pathway plays a role in breast cancer (BC) pathogenesis and emerging evidence suggests the androgen receptor (AR) is a therapeutic target. TBCRC011 established safety and efficacy of inhibiting AR with bicalutamide (B) in patients (pts) with androgen AR+/ER/PgR- metastatic BC (MBC). Treatment with B at 150 mg oral daily demonstrated a clinical benefit rate (CBR) of 19% in this population. The rationale for combining palbociclib (P) with AR blockade stems from prior work in ER+ MBC. P is an oral, selective inhibitor of CDK4/6 activity which significantly improved median progression-free survival (PFS) in combination with letrozole compared to letrozole monotherapy for the treatment of postmenopausal pts with ER+ MBC in the first-line setting. Consistent with preclinical data, P has been shown to reduce growth of AR+ ER/PgR- MDA-MB-453 breast cancer cells via reduced Rb phosphorylation. It has been shown that AR+ TNBC expresses a luminal profile and has intact Rb protein, the target of palbociclib activity. Therefore, we hypothesize that P will increase the efficacy of B in pts with metastatic AR+ TNBC. NCT02605486.
Methods: Pts with AR+ (IHC ≥ 1%)/ER any/HER2(-) MBC on central review at MSK were eligible if met following criteria: ECOG ≤2, postmenopausal, no limit to prior regimens. Pts with ER+ BC must have had 1 prior endocrine therapy. Treatment: B orally daily and P orally daily 3 weeks on 1 week off. DLT period = 28 days. Pts are evaluated for toxicity every 2-4 weeks and for response every 8 weeks. Phase I standard 3+3 design with 3 dose escalations. The primary objective of the phase I portion of the study is to determine the recommended phase II dose of P in combination with B. Plasma for pharmacokinetics (PK) was collected throughout the study.
Results: As of 5/11/17, 15 pts with AR+ MBC were enrolled to the phase I portion. Target accrual has been met for the phase I and has since closed. No DLTs were reported in any of the dose escalation cohorts. The maximum tolerated dose was determined to be B 150 mg daily and P 125 mg daily for 21 days in a 28 day cycle. Treatment has been well tolerated with no related Grade 4 or 5 adverse events (AEs). The most common grade 3 significant AEs were hematologic including neutropenia n =5, leukopenia n= 4, and lymphocytopenia n=3 and thought to be related to P. One Grade 4 hypercalcemia led to hospitalization and was deemed related to disease progression. Median time on study was 8 weeks (2-47 weeks). One patient from the phase I remains on study. PK analysis is ongoing and will be presented, including drug-drug interaction data.
Conclusions: The combination of B+P has been well tolerated with no unexpected toxicity observed. Updated safety, response, and PK data will be presented. Enrollment on phase II is ongoing.
Citation Format: Gucalp A, Edelweiss M, Patil S, Gounder MM, Feigin KN, Corben A, Arumov A, Traina TA. Phase I/II trial of palbociclib in combination with bicalutamide for the treatment of androgen receptor (AR)+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-04.