SIU 2017: Optimal Sequencing and Monitoring of Androgen Receptor (AR) Pathway Inhibitors in mCRPC

Lisbon, Portugal ( Dr. Gleave began his presentation with the fact that in hormone naïve prostate cancer, it has recently been shown in the STAMPEDE and LATITUDE trials that Abiraterone and prednisone was a well-tolerated treatment. Furthermore it improved overall survival by 37%, failure free survival by 70%, and symptomatic skeletal events by 30%-55%. These studies have demonstrated that abiraterone and prednisone should be the standard of care for men starting long term ADT.

Androgen receptor (AR) pathway inhibitors have re-defined prostate cancer (PC) landscape, moved up to M1 castrate sensitive prostate cancer (mCSPC), prolonging overall survival. Taxans have now been displaced to 2nd and 3rd line mCRPC, but also upstream in combo with ADT in mCSPC.

Dr. Gleave brought up the question if we should use abiraterone or enzalutamide as first line treatment in mCRPC. The outcomes from the corresponding trials assessing abiraterone and enzalutamide (Cou-302, and PREVAIL, respectively) were similar. It is important to remember that the adverse events profiles are different between the 2 drugs. While abiraterone requires monitoring of liver function test and concomitant use of prednisone, enzalutamide can cause a lower threshold for seizures, fatigue and cognitive changes. TO DATE, the choice between the 2 drugs is usually decided by doctor preference, patient factors, and cost/availability. Up until now, there has been no comparative controlled data.

Some important treatment sequencing questions in mCRPC were then discussed. Firstly, are there any mCRPC patients who may benefit from chemotherapy as a first line treatment? Second, should abiraterone/enzalutamide be sequenced or go immediately to chemotherapy? And lastly, are there any predictive factors that help. It is important to remember that 10-20% of CRPC patients have primary resistance to abiraterone and enzalutamide. There is a CRPC prognostic index, analyzed from the Cou-301 study, constructed from several clinical and lab tests that can give us some predictive information whether the patient will react positively to abiraterone. Additionally, there are genomic biomarkers associated with poor response to AR pathway inhibitors (ARPI). These include amplification of AR and AR variants, which are associated with poor response to ARPI.

The next important step is whether abiraterone/enzalutamide should be sequenced, or do we need to switch to chemotherapy after 1st line treatment in CRPC. Thus far there has been only retrospective data showing that despite the fact that the 2 drugs share a common mechanisms of resistance, there is low activity with abiraterone after enzalutamide while there is more activity with enzalutamide after abiraterone, although no overall survival benefit was noted.

Dr. Gleave then moved on to discuss the current study performed in Vancouver and led by Dr. K. Chi comparing abiraterone to enzalutamide. This is a phase 2 multicenter study designed to validate ctDNA alterations as prognostic and predictive biomarkers in the comparison of abiraterone and enzalutamide. In this prospective study 202 patients were randomized to receive either abiraterone and prednisone or enzalutamide as 1st line therapy. When PSA progressed the patients were crossed over to receive the other treatment, and continued until clinical progression. Whole blood ctDNA and RNA were collected at randomization, PSA progression before crossover, and at final clinical progression.

Preliminary results of this study shown by Dr. Gleave demonstrated that in the abiraterone group best PSA decline of over 50% occurred in 55% of patients compared to 77% in the enzalutamide group, p=0.0012. However, there was no statistically significant difference in time to progression and time to PSA progression between both treatments. Other important preliminary findings that Dr. Gleave could share included the fact that 56.5% of patients had AR amplification, 12.2% had an AR mutation, and other mutations were demonstrated at a rate that was consistent with previous studies.

Dr. Gleave summarized his interesting presentation by stating that additional new drugs are needed that target direct and indirect AR reactivation. This includes the AR DNA binding domain. ADT and abiraterone is the new standard of care in mCRPC. Molecular sub-classification of mCRPC is key to stratify appropriate treatment. We need to understand which patients do badly with abiraterone and enzalutamide, and which patients benefit from sequencing abiraterone and enzalutamide. Plasma ctDNA liquid biopsies enable real time monitoring of treatment induced mutation adaptations in mCRPC and this should be used in future studies.

Presented by: Martin Gleave

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre.Twitter: @GoldbergHanan at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal
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