AUA 2019: Ramon Guiteras Lecture: More Arrows in Our Quiver—Targeting the Adaptive Molecular Landscape of Advanced Prostate Cancer
AR genomic and intratumor steroidogenesis support AR re-activation. Recent studies show that moving docetaxel or ARPIs earlier in combination with ADT improves outcomes. Studies have also found that combining or sequencing abiraterone or enzalutamide does not provide oncologic benefits due to cross-resistance and complex pathway interactions. Thus, molecular sub-classification of tumors is critical, and stratified approaches to treatment are prudent. With the identification of biomarkers for advanced prostate cancer, we will gain the ability to choose the order of treatment (ARPI versus docetaxel for castrate-sensitive prostate cancer), select specific targeted therapies or immunotherapy, define and detect treatment resistance and design rational combination therapies.
Genomic profiling can be used to define adaptive induction of compensatory pathways in castrate-resistant prostate cancer (CRPC). Studies have shown that as prostate cancer cells are stressed by therapies, tumors may first respond with regression, but advanced tumors develop clonal evolution and adaptive responses leading to progression and castration resistance. These stress pathways may be AR-driven or work through stress pathways, growth factor signaling, or developmental pathways. Biopsies of metastatic CRPC show numerous changes including those of DNA repair, lineage plasticity, AR signaling, PI3K/AKT pathway changes, and cell cycle changes. Given the known and extensive heterogeneity of tumor sites in a single patient, there are inherent limitations to gene sequencing of standard tissue biopsies. Dr. Gleave’s team is studying circulating tumor DNA (ctDNA) through “liquid biopsies” as they may represent the alterations more completely. Indeed, they have found that ctDNA is highly concordant with mCRPC tissue biopsy and is more cost effective.
Recent studies have demonstrated advantages for starting treatment with abiraterone over enzalutamide because patients who fail abiraterone treatment have improved response with subsequent enzalutamide; the same is not true of the converse treatment sequence.
Treatment-induced genomic alterations in ARs drive resistance. Genomic pressures induced via ligand binding can lead to AR amplification or truncated variants which leads to negative prognosis. Different mutations involve under different treatment pressures; the 702H mutation evolves under prednisone, and many others exist. But they may respond to other treatments. Genomic alterations identify drugs that can be repurposed, however. For example, Olaparib, a PARP inhibitor was combined with abiraterone in a phase 2 trial which showed improvements regardless of whether patients were biomarker positive or negative. The overall survival (OS) was not affected as the study was underpowered. As we move forward, molecular sub-classification coupled with availability of drugs will stratify our approaches to treatment.
Highly conserved stress responses coopted by cancer cells result in selective mRNA translation. Neuroendocrine prostate cancer (NEPC) is associated with liver metastases, low PSA, high mitotic levels and conversion to small cell entities. The transformed tumors are genetically identical, but there are epigenetic changes and expression of select mRNA, distinguishing the new tumor form. New transcription factors activate down-stream pathways, requiring new therapeutic targets.
The lecture summarized the following. Sequencing abiraterone and enzalutamide in CRPC is not effective with the exception of patients with specific mutations. Combining abiraterone and enzalutamide upfront is not effective (Alliance trial), and, adding abiraterone at the time of enzalutamide resistance is not effective (PLATO trial). Combination co-targeting crosstalk pathways are potentially effective (ARPI + chemotherapy, ARPI + PARPi, etc.). Earlier targeting before resistance develops in castrate-sensitive prostate cancer may be beneficial. AR is the key driver pre- and post-ADT, and post-ARPI CRPC. Co-targeting adaptive pathway activation is a promising approach.
Presented by: Martin Gleave, Director, Department of Urologic Sciences, Vancouver Prostate Centre, Vancouver, British Columbia, Canada
Written by: Selma Masic, MD, Urologic Oncology Fellow (SUO), Fox Chase Cancer Center, @selmasic at AUA 2019 at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois