Abstract CT031: A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer (mCRPC)
Authors: Fong Lawrence , Morris Michael , Armstrong Andrew , Petrylak Daniel , Vaishampayan Ulka , Alva Ajjai , Hoffman-Censits Jean , Sarkar Indrani , Carroll Susheela , Schiff Christina , Sartor Oliver 
Published: July 2017

Abstract
Background: In patients (pts) with mCRPC, bone metastases (mets) occur up to 80% of the time and are a significant cause of morbidity and mortality. Radium-223 dichloride (Ra-223) is a targeted α-emitter and extends overall survival (OS) in mCRPC pts with symptomatic bone mets. While several therapies, including Ra-223, have recently been approved for mCRPC, pts ultimately develop resistance and progressive disease. Therefore, there is a high unmet need for new treatments for mCRPC pts. Atezolizumab (atezo) is a humanized mAb that targets PD-L1 and blocks its interaction with its receptors, PD-1 and B7.1, which is expected to enhance T-cell responses and improve anti-tumor activity. A pre-clinical study found that tumor and dendritic cells have higher PD-L1 expression after ionizing radiation (IR) exposure and that combining anti-PD-L1 therapy with IR enhanced the inhibition of tumor growth. Radiotherapy leads to immune modulation and may help prime an immune response by releasing tumor-associated antigens that may target tumors distant from the local radiation field (i.e., abscopal effect). These data support the hypothesis that atezo + Ra-223 may be an effective therapy for CRPC pts with bone and soft tissue mets.
Methods: A phase Ib clinical trial (NCT02814669) is being conducted to assess the safety and tolerability of atezo + Ra-223 in pts with mCRPC after progression on an androgen pathway inhibitor and to identify a recommended treatment schedule. Pts will have mCRPC with at least 2 bone mets and either measurable visceral (non-liver) mets or lymphadenopathy. Eligibility criteria include ECOG PS 0-1, progression on an androgen pathway inhibitor, and soft tissue disease amenable for serial biopsy. Exclusion criteria include small cell or neuroendocrine prostate cancer, autoimmune disease, eligible for and willing to receive treatment with taxanes, and prior treatment with Ra-223. Pts will receive atezo (840 mg q2w) and Ra-223 (55 kBq/kg q4w). The study includes a cohort phase, to evaluate a concurrent dosing regimen, and if safe and tolerable, a randomization phase to compare concurrent and staggered dosing. Regimens that are safe and tolerable may undergo expanded enrollment. A recommended schedule will be based on incidence of dose-limiting toxicities during first cycle of combination treatment. A preliminary assessment of efficacy will include ORR per RECIST v1.1, DOR, rPFS, OS, and PSA response rate. Approximately 45 pts will initially be enrolled in the United States.
Citation Format: Lawrence Fong, Michael Morris, Andrew Armstrong, Daniel Petrylak, Ulka Vaishampayan, Ajjai Alva, Jean Hoffman-Censits, Indrani Sarkar, Susheela Carroll, Christina Schiff, Oliver Sartor. A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT031. doi:10.1158/1538-7445.AM2017-CT031