Although the EAU guidelines  are explicit about diagnosing CRPC after a testosterone < 50 ng/mL in the setting of an increasing PSA and offering docetaxel in patients fit for chemotherapy, there are no recommendations of further sequencing agents, either pre- or post-docetaxel.
As Dr. Tombal notes, the androgen receptor is the main driver of the adaptive mechanism from castration sensitive to the castration resistant state. Certainly, this is evident when assessing the pre-chemotherapy abiraterone (COU-AA-302 ) and enzalutamide (PREVAIL ) PSA change from baseline curves, noting distinct changes when primary resistance to AR-targeted agents prior to chemotherapy occurs. Dr. Tombal notes that when the expert panel at the Advanced Prostate Cancer Consensus meeting earlier this year were posed the question as to what their preferred first-line mCRPC treatment option was in the majority of asymptomatic or minimally symptomatic men who did not received docetaxel, 86% noted that they would give abiraterone or enzalutamide . Dr. Tombal importantly highlights that the sequence starting with enzalutamide or abiraterone increases survival, provided that you manage to administer the other treatments after resistance to these agents occurs.
In Dr. Tombal’s mind, enzalutamide or abiraterone are the reference treatments of early mCRPC, however there are several challenges we must keep in mind:
(i) How early is early?
On a post-hoc analysis of the PREVAIL data, Evans et al. note that when stratifying patients by degree of bone metastasis (<4 vs ≥4), both subgroups had an OS benefit when receiving enzalutamide compared to placebo alone. However, among patients with ≥4 bone metastasis, those with nonvisceral only disease achieved a similar OS benefit with enzalutamide as those with <4 bone metastases . Thus, it appears that degree of disease burden impacts the efficacy and thus enzalutamide (and abiraterone) should be given prior to extensive visceral disease.
(ii) Is there still a role for hormonal therapies without proven benefit?
In the COU-AA-302 trial, 100% of patients received antiandrogen therapy prior to entering the trial, whereas 65% of patients in PREVAIL received prior antiandrogen therapy. Results from the TERRAIN study , randomizing men with mCRPC to either ADT + enzalutamide (n=184) or bicalutamide (n=191), found that patients receiving enzalutamide had a significantly improved median PFS (15.7 months) compared to bicalutamide (5.8 months; HR 0.44, 95%CI 0.34-0.57). Similar results were found in the STRIVE trial randomizing men with nonmetastatic and metastatic CRPC to either ADT + enzalutamide or bicalutamide, finding that enzalutamide reduced the risk of progression or death by 76% compared to bicalutamide (HR 0.24, 95%CI 0.18-0.32) .
(iii) When should we use chemotherapy instead?
As Dr. Tombal notes, chemotherapy remains essential to the management of CRPC, since AR-independent prostate cancer may be the dominant form of cancer at diagnosis (primary resistance). According to a European Expert Consensus panel , there was strong consensus that patients with short duration of responses (<1 year) to first-line ADT could be used as an indicator of increased risk for primary resistance to AR-targeted agents. Certainly, this opens the door for chemotherapy, but also darolutamide, a nonsteroidal antiandrogen with selective high affinity for the AR receptor. In a phase I/II trial, darolutamide showed activity in chemotherapy/abiraterone naïve and post-abiraterone mCRPC patients .
Dr. Tombal concluded his thought provoking presentation with a quote answering the question as to what the best sequence of therapy is: “The best sequence is the sequence in which you secure that patients have a chance to receive each of the drugs when they are the most likely to benefit from them.”
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Speaker: Bertrand Tombal, Cliniques Universitaires Saint Luc, Brussels, Belgium
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the EAU - Update on Prostate Cancer – September 15-16, 2017 - Vienna, Austria