ESMO 2017: The Evolving Landscape of Treating Advanced Prostate Cancer
(1) Sequencing in CRPC
COU-301 [1] and COU-302 [2] demonstrated that abiraterone significantly prolonged overall survival (OS) in both the pre- and post-docetaxel populations, followed by AFFIRM [3] and PREVAIL [4] demonstrating similar result for enzalutamide in this same population. Subsequently, ALSYMPICA [5] showed that radium-223 demonstrated significantly improved OS regardless of prior docetaxel use. Over the past 15 years, several compounds have demonstrated OS benefit in the mCRPC setting, but we are still elucidating the correct sequence of treatment:
(2) Role of the bone in mCRPC
Bone metastases can result in serious and debilitating skeletal-related events (SREs). SREs are typically defined as radiation to the bone (most common), pathologic fracture, spinal cord compression and surgery to the bone. Furthermore, SREs increase the risk of subsequent SREs. Thus, it is crucial to interrupt the vicious cycle of bone metastases, which includes a complex network of pathways between the tumor cells, osteoblasts and osteoclasts. Several bone protective agents have proven useful in this setting, including denosumab (targeting the RANK ligand), bisphosphonates (targeting the osteoclast), and to a lesser extent ETaR inhibitors (targeting ET1 from the tumor cells).
(3) Can we predict response to new hormone therapies?
The development of resistant to antihormonal therapies can occur through a variety of mechanisms, including: (i) overexpression of CYP17, (ii) activating mutations in ligand-binding domain of the androgen receptor, (iii) glucocorticoid receptor-mediated transcriptional activation, (iv) activation of PI3K/Akt signaling, and (v) androgen receptor splice variants. Specifically, in the AR-V7 variant, there is a lack of ligand binding domain, providing therapeutic challenges. The AR-V7 mutation is highly prevalent in patients with CRPC after treatment with abiraterone and enzalutamide. In a study of AR-V7 prevalence in 62 patients with mCRPC, 11.6% occurred in patients with pre-enzalutamide and pre-abiraterone treatment, 25.0% in patients with post-enzalutamide treatment only, 51.2% in patients with post-abiraterone treatment only, and 66.7% in patients with post-enzalutamide and post-abiraterone treatment [6].
(4) The impact of STAMPEDE, CHAARTED, and LATITUDE on treatment in both hormone naïve prostate cancer (HNPC) and CRPC
It has been well established that docetaxel + ADT [7,8] or abiraterone + ADT [9,10] improve multiple survival endpoints compared to ADT alone in men with HNPC. However, as of this meeting when Dr. James’ group presented head to head data comparing ADT + docetaxel vs ADT + abiraterone, we now have additional information in this space: (i) strong evidence favoring abiraterone for FFS and PFS, (ii) weak evidence favoring abiraterone on metastatic PFS, (iii) no good evidence on survival, CSS and symptomatic skeletal event rate.
Dr. James concluded stating that the management of CRPC is quickly changing. However, there are important questions remaining over sequencing and predictive markers. The migration of therapies from CRPC to HNPC will likely impact how CRPC is treated in the future. Finally, the success of docetaxel and abiraterone combined with ADT show that we should be continuing to explore combinatorial options in the HNPC and CRPC space.
Speaker: Nicholas D. James, University of Birmingham, Birmingham, United Kingdom
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
References:
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