Identification of Patients Sensitive to Chemotherapy

Chicago—Loss of the retinoblastoma tumor suppressor function has been identified as a major factor in the development of castrate-resistant prostate cancer (CRPC). The expression of the androgen receptor is under stringent retinoblastoma control, and tumors that are devoid of retinoblastoma function are hypersensitive to chemotherapy treatment. Based on exploratory analyses to evaluate baseline N-terminal androgen receptor expression in circulating tumor cells (CTCs) in men with chemotherapy-naïve CRPC and correlated to changes in prostate-specific antigen (PSA), Susan F. Slovin, MD, and colleagues developed the hypothesis that this biomarker may identify patients who are sensitive to chemotherapy.

The researchers recently conducted a multicenter phase 2 randomized trial of abiraterone acetate plus prednisone (AA-Arm 1) or combination abiraterone acetate and standard doses of cabazitaxel (AA/CBZ-Arm 2). Results were reported during a poster session at the 2017 ASCO Annual Meeting in a poster titled Circulating Tumor Cells (CTCs) N-Terminal Androgen Receptor Expression to Identify Patients with Castrate-Resistant Prostate Cancer (CTCP) Who Are More Sensitive to Chemotherapy.

Patients on abiraterone acetate plus prednisone received cabazitaxel on progression. Baseline CTCs were obtained on all patients and N-terminal androgen receptor expression was performed by Epic Sciences. Positive androgen receptor N-terminal expression was based on the presence of at least one CTC or CK cell with androgen receptor N-terminal signal expression above the 3.0 positivity threshold. At baseline, serial PSAs were determined, and every 3 weeks thereafter; regular laboratory tests and imaging were performed every 12 weeks.

As of the publication of the poster, 42 of 80 patients have been enrolled: 22 have been randomized to Arm 1 and 20 to Arm 2. Both regimens have been well tolerated: eight of the 42 patients (19%) have experienced treatment-related grade 3 or 4 toxicities. CTC analysis has been performed on blood from 35 patients; 27 of the 35 (77%) had detectable CTCs, and 11 of the 35 (11%) had androgen receptor overexpression. Of the patients with positive androgen receptor N-terminal expression CTCs, one of five were treated with abiraterone acetate plus prednisone. Five of six patients treated with abiraterone acetate plus prednisone in combination with cabazitaxel had a PSA decline >50% from baseline.

“Real-time CTC analysis of N-terminal androgen receptor expression was feasible and data suggest that this may identify a cohort of patients who may benefit from the combination of cabazitaxel with abiraterone acetate. Further studies are ongoing to evaluate whether cellular heterogeneity and retinoblastoma expression in CTCs play a role in identifying patients who would benefit from chemotherapy,” the researchers said.

Source: Slovin SF, Knudsen KE, Halabi S, et al. Circulating tumor cells (CTCs) N-terminal androgen receptor expression to identify patients (pts) with castrate resistant prostate cancer (CRPC) who are more sensitive to chemotherapy. Abstract of a poster presented at the 2017 American Society of Clinical Oncology Annual Meeting, June 5, 2017, Chicago, Illinois. This trial is coordinated by the Prostate Cancer Clinical Trials Consortium, LLC, and funded by Sanofi US Services Inc. and Prostate Cancer Foundation. Clinical Trial information: NCT02218606