Exploratory Biomarkers That Predict For Clinical Outcomes In A Phase Ii Trial With Ipilimumab Plus Finite Androgen Deprivation Therapy For Metastatic Non-Castrate Prostate Cancer

Background: Androgen deprivation therapy (ADT) is a standard treatment that, although not curative, often induces dramatic responses in patients with advanced prostate cancer by inducing tumor cell death, which may provoke antigen release to initiate T cell responses. Ipilimumab blocks the inhibitory immune checkpoint, CTLA-4, which enhances T cell responses and induces both clinical benefit and unique toxicities in a subset of patients with advanced cancer. We designed a clinical study combining ipilimumab with finite ADT in men with metastatic prostate cancer to estimate therapeutic efficacy, determine safety, and identify predictive biomarkers for clinical outcomes. Methods: We screened 30 patients and enrolled 27 patients between July, 2011 and June, 2013 for an open-labelled, single-center, Phase II study of ipilimumab plus finite ADT as first-line therapy for metastatic non-castrate prostate cancer. Eligible patients had histological confirmation of prostate carcinoma and radiographic documentation of metastatic disease. ADT was given for a finite duration of eight months with concurrent ipilimumab (10 mg/kg) for up to four doses, each given four-weeks apart. The primary endpoint was the proportion of patients with undetectable PSA (≤0.2 ng/mL) at seven months post-treatment initiation with ADT. In addition, we performed comprehensive immune monitoring of the peripheral blood using multi-parametric flow cytometry and next-generation sequencing of T cell receptors. Findings: All 27 of the enrolled patients were evaluable for safety and toxicity, and 24 of these patients were evaluable for therapeutic effectiveness. Ten of the 24 (42%) patients achieved the primary endpoint of undetectable PSA levels at seven months post-treatment initiation. The median time to PSA progression was 10.0 (IQR 5.9-13.3) months from treatment initiation, and one (4%) of the 24 patients continues to have a PSA response that is ongoing for 40.7 months. The trial was closed as prespecified due to grade 3 toxicities that occurred in 12 (44%) of 27 patients. The most common grade 3 adverse events were transaminitis, colitis/diarrhea, and hypophysitis. Immunological biomarkers were identified that potentially predict for clinical benefit and grade 3 toxicities in this small study. No grade 4 or 5 toxicities were observed. Interpretation: Although the combination of 10 mg/kg ipilimumab plus finite ADT led to toxicities that met a prespecified endpoint for closure of the trial, our current knowledge and experience about combination therapies and dose of ipilimumab leads us to postulate that additional clinical trials evaluating ipilimumab at 3 mg/kg plus ADT is warranted. In addition, we identified candidate immunological biomarkers that need to be further tested as predictive markers of clinical benefit and grade 3 toxicities. Citation Format: Sumit K. Subudhi, Ana Aparicio, Jianjun Gao, Amado Zurita-Saavedra, John C. Araujo, Christopher J. Logothetis, Korivi R. Brinda, Jim P. Allison, Luis Vence, Ryan O. Emerson, Erik Yusko, Marissa Vignali, Harlan S. Robins, Jingjing Sun, Padmanee Sharma. Exploratory biomarkers that predict for clinical outcomes in a Phase II trial with ipilimumab plus finite androgen deprivation therapy for metastatic non-castrate prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1402.