She began by highlighting the progression of hormonal treatment strategies in the treatment of metastatic castration sensitive prostate cancer over the past seven decades:
1. Bilateral orchiectomy versus medical castration
2. Gonadal suppression versus peripheral blockade
3. LHRH-agonists versus antagonists
4. Combined androgen blockade versus gonadal suppression alone
5. The role of bone targeting therapy in addition to ADT
6. Intermittent versus continuous ADT
She then highlighted molecular pathways in the progression of hormone-sensitive to castration-resistant disease including clonal selection and adaptation. There are important androgen-receptor dependent mechanisms including gene amplification and mutation. Additionally, there are non-AR dependent pathways that depend on alteration in survival pathways which bypass the AR. As a result, there are a plethora of pathways and targets for which agents have been developed and tested. Dr. Hussain highlighted 8 pathways and their targeting agents as shown below:
Following decades of stagnation, Dr. Hussain highlighted the massive proliferation of available and efficacious agents which have become available since 2010.
While typically developed and tested at the very end of the prostate cancer trajectory (typically beginning in the post-chemotherapy castration resistant space), these therapies have been advanced to earlier disease states. Following this principle of “earlier is better”, Dr. Hussain highlighted evidence from CHAARTED (and validated in STAMPEDE), that use of docetaxel chemotherapy in hormone-sensitive patients, prior to the development of castration resistance, conferred a large survival benefit, though longer follow-up subsequently showed that this was restricted to patients with high-volume disease.
The second example she provided of the “earlier is better” philosophy is the use of AR-targeting agents in non-metastatic castration-resistant prostate cancer. Based on the idea of a “window of opportunity”, Dr. Hussain argued that these agents may be more effective in patients with a lower tumor burden. Further, delaying metastasis was, in and of itself, a valuable and clinically relevant endpoint in her view.
She then highlighted the phase III data supporting each of apalutamide (SPARTAN), enzalutamide (PROSPER), and darolutamide (ARAMIS). Each of these has been covered in detail in previous UroToday coverage1,2 but a brief overview is given below:
She concluded by assessing what she saw as “next” for advanced prostate cancer. This fell into four categories:
1. Maximizing anti-tumor effect
2. Personalizing treatment
3. Improving imaging
4. Enhance survivorship and address cost/value considerations
With respect to personalizing treatment, she highlighted data from the SU2C cohort demonstrating that more than 20% of patients with mCRPC have aberrations in the DNA repair pathway. These aberrations, as discussed in Dr. Helfand’s talk as well, confer particular sensitivity to targeted agents such as olaparib.
These mutations are also associated with response to first-line abiraterone and enzalutamide.
Additionally, combinations of olaparib and abiraterone have been proven effective in all comers, with particular benefit among patients with mismatch repair defects. Concluding, she highlighted further trials underway to assess the optimal treatment approach for these patients.
Presented by: Maha Hussain, MD, FACP, FASCO, is the Genevieve Teuton Professor of Medicine in the Division of Hematology Oncology, Department of Medicine, and the Deputy Director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, Chicago, Illinois
Written by: Christopher J.D. Wallis, Urology Resident, University of Toronto, Contact: @WallisCJD on Twitter
References:
1. Chandrasekar, T. (2018). ASCO GU 2018: First Presentation - SPARTAN: A Study of Apalutamide (ARN-509) in Men with Non-Metastatic Castration-resistant Prostate Cancer. [online] Urotoday.com. [Accessed 7 May 2019].
2. Chandrasekar,, T. (2018). ASCO GU 2018: First Presentation - PROSPER: Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC). [online] Urotoday.com. [Accessed 7 May 2019].