ASCO GU 2017: Advances in the Understanding and Treatment of Androgen-Receptor-Indifferent Prostate Cancer

Orlando, Florida USA (UroToday.com) Dr. Ana Aparicio discussed the implications of androgen-receptor (AR)-indifferent prostate cancer (PC), which is defined as morphologically and biologically heterogeneous carcinomas with a shared lack of responsiveness to androgen signaling and inhibition. Historically, only small-cell morphology has been considered to be AR-indifferent, but biopsy studies reveal that even patients with presumed small-cell PC show evidence of adenocarcinoma in tumor specimens. Thus, a new clinical definition of this AR-indifferent cancer has been adopted. These cancers are characterized by small-cell morphology or, presenting with visceral metastasis only, low prostate-specific antigen relative to metastatic burden, neuroendocrine markers, and early castration resistance. The incidence of these AR-indifferent cancers in castration-resistant patients can be as high as 20% and account of 10% of newly diagnosed advanced PCs.

When used in a recent trial, the above criteria were used to treat people with castration-resistant PC, none with small-cell histology. Docetaxel plus carboplatin helped assess whether these presumed AR-indifferent patients were more likely to respond to platinum-based chemotherapy (PBC). The phase-II prospective trial indicated that 87.5% of individuals exhibited a favorable response to PBC.

Given the above results, several groups have begun to perform molecular characterization of clinically AR-indifferent PC. These studies have shown that alterations in tumor suppressor genes are common, specifically Tp53, RB-1, and PTEN pathways. These results correlate well with prior genetic analysis done on small-cell PCs, which have shown similar alterations in tumor suppressor genes. This finding has been further supported by genetically engineered mouse models that display T53 and RB-1 losses, resulting in the increase in the EZH2 and Sox2 expression, which is a well-known pathway for androgen resistance.

Correlation of the findings was performed clinically by genetically characterizing patients treated with PBC who had shown evidence of AR-indifferent clinical attributes. The study indicated that patients who presented with two or more defects in the Tp53, RB-1, or PTEN pathways had a better response to PBC.

The field’s future is bright, and it may help further risk stratify patients into AR-indifferent categories earlier and, thus, allow for these patients to receive early PBC. Dr. Aparicio introduced the DynAMO Trial, which might improve the treatment of patients with castration-resistant PC by allowing an early identification of the AR-indifferent cohort. In the study, all patients would receive abiraterone + apalutamide for 8 weeks. Depending on marker decline, they would be placed on ipilimumab if they exhibited a satisfactory response or on cabazitaxel + carboplatin if there was an unsatisfactory response. The study has currently accrued 56 patients, and early data appear to be showing a benefit in those treated with early PBC.

Presented By: Ana Aparicio, MD, MD Anderson Cancer Center, Houston, TX

Written By: Andres F. Correa, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center

at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA

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