Abstract IA06: Co-Targeting cell cycle and androgen signaling to personalize therapy for hormone dependent prostate cancer

Abstract

Abstract Prostate cancer (PC) is an androgen driven and dependent disease and androgen deprivation therapy (ADT) is the standard for patients with metastatic hormone sensitive disease. Despite a high response rate, most patients will progress to castration resistance. The expanding molecular knowledge highlights the biologic heterogeneity and adaptive capacity of PC, and provides the rationale for a preemptive multi-targeted therapeutic strategy. Compelling support for the latter strategy is provided by recent data from two randomized trials demonstrating an unprecedented impact on survival with the addition of docetaxel to ADT. Androgens drive proliferation of PC cells via upregulation of cyclin D which complexes with the cyclin-dependent protein kinases 4/6 (CDK4/6) resulting in phosphorylation of retinoblastoma (Rb) tumor suppressor protein and G1/S progression. Alterations in this pathway contribute to progression to castration-resistance. Palbociclib is a novel specific CDK4/ 6 inhibitor which was recently approved in combination with letrozole for postmenopausal women with ER +, HER2 negative advanced breast cancer. In preclinical prostate cancer models, palbociclib inhibited proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner. Current data indicate that wild-type Rb expression is present in in 95% vs 75% of patients with newly diagnosed vs metastatic castration resistant PC respectively. We estimate that 80-90% of early metastatic hormone-sensitive PC will harbor intact Rb. Based on the biologic and preclinical data, we developed a multicenter randomized phase II clinical trial (NCT02059213) to test the hypothesis that adding palbociclib to ADT in patients with newly metastatic Rb-positive PC will significantly increase the efficacy of ADT. Patients (n = 60) with new metastatic hormone sensitive PC and Rb intact tumors based on metastatic biopsy are stratified by disease extent and randomized (1:2) to ADT or ADT+ palbociclib. Primary endpoint is confirmed prostate specific antigen (PSA) response (< 4 ng/mL) after 28 weeks of therapy. With 20 patients randomized to ADT and 40 randomized to ADT plus palbociclib there will be a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher's exact test. Secondary endpoints: safety and tolerability of ADT + palbociclib, rate of undetectable PSA (< 0.2ng/mL), biochemical and clinical progression-free survival, overall PSA and radiographic response rates, assessment of biomarkers which predict therapy response (circulating DNA and tumor cells, tumor protein and transcriptome analysis) and to establish a repository of metastatic hormone sensitive prostate tumor samples. To date 39 patients have been registered and underwent tumor metastatic disease biopsy (soft tissue 26, bone 13). 2 patients were Rb negative and 5 had inadequate tissue. 32 patients have been randomized to ADT (11 patients) or ADT + palbociclib (21 patients). The study is in progress. Support: Movember-PCF Challenge Award, Pfizer. Citation Format: Maha Hussain, Phillip L. Palmbos1, Scott A. Tomlins1, Stephanie Daignault-Newton, Neeraj Agarwal, Przemyslaw Twardowski, Alicia K. Morgans, Emmanuel S. Antonarakis, Karen E. Knudsen, Felix Y. Feng. Co-Targeting cell cycle and androgen signaling to personalize therapy for hormone dependent prostate cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA06.