The development of combination antitumor regimens is standard oncology procedure and has resulted in the developments of many curative regimens - think ABVD for Hodgkins, R-CHOP for DLBCL or BEP for testicular cancer. These combinations were developed, however, based on the idea that a matrix of nonoverlapping toxicity and nonoverlapping mechanisms of action could be harnessed to deliver the most anti-cancer bang for the lowest buck.
That was not really the idea that came to mind when combining abiraterone and enzalutamide. In this instance, the idea was more based on the principle that, if a little AR suppression is good, then a lot of AR suppression may be better. it is not about distinct mechanisms, it is about a greater hit on one mechanism.
The scientific rationale behind this was reasonably sound, however. We have known for some time that one important, if not critical, mechanism of resistance to androgen suppression therapy is an amplification of the AR. If AR amplification occurred in the setting of ‘standard’ LHRH-based ADT it is also likely to occur in the setting of ‘enhanced” Abiraterone-based ADT, thus the addition of enzalutamide, putatively designed to target the amplified AR, made sense.
Similarly, some data existed to show that resistance to first-line AR-targeted drugs came from a rise in serum androgens and even data that I have published that has shown that higher androgen levels in CRPC are prognostic - paradoxically – of a better outcome. Presumably, this arises from the therapeutic potential of lowering androgens with drugs like abiraterone or ketoconazole, where it was initially shown.
Now we are beginning to get a peek at the clinical output of these hypotheses. Three studies will soon inform this situation in three different scenarios:
Scenario ONE: Abi+Enza in Enza Resistance
Does the addition of Abiraterone at the time of enzalutamide resistance allow us to ‘recapture’ a response? This was the hypothesis behind the PLATO trial, recently reported by Gert Attard in the Journal of Clinical Oncology (NCT01995513; Attard et al JCO 2018). In this study patients experiencing PSA only progression on Enzalutamide were randomized in a 1:1 fashion to receive abiraterone plus Enzalutamide or placebo plus Abiraterone. The results showed no significant difference in outcome in terms of PFS and only a handful of patients experienced a PSA decline ( only 1-2% in both groups) and only a few more had any decline in PSA.
So, a negative study. Resistance to one is tantamount to resistance to the other. That’s the conclusion for this. Don’t ADD abiraterone to enza when patients experience progression of disease on Enza. We haven’t studied prospectively the other scenario of adding ENZA to abiraterone. But I’m not sure that is worth our clinical trial resources at this point.
Scenario TWO: Front line therapy for CRPC:
This is being tested in the US Cooperative group trial A031203 which is likely to report in the next year. No preliminary results have been presented and the study will report on a definitive overall survival endpoint. Failure of the combination at the point of resistance in PLATO does not mean that the upfront combination will be negative. In this scenario, we may see that the initial “double hit” on the tumor from the combined approach may induce a deeper response which, if carried forward, will impact long-term outcomes. Initial data from an MD Anderson study did suggest that the proportion of patients experiencing a 90% decline in PSA, for example, was higher with the combination than what we see with these drugs alone.
Scenario Three: Front line therapy for HSPC:
The Abi/Enza combination is an arm of the everlasting STAMPEDE trial and will focus on newly diagnosed M1 patients and even some with locally advanced disease. We don’t yet know when it will report. It is for HSPC so again, slightly different biology. The tumor may be less adapted and resistant. As with the scenario pertaining to scenario two above this approach should be considered a focus on the greater initial ‘remission induction’ that could be experienced with the combination.
So, even though these drugs are beginning to feel like they are getting old, our knowledge of the effects of combining them is still beginning to emerge. Let us hope that if the other studies are negative that we can learn from them, about PK variability, pharmacogenomics, novel methods of resistance, etc.
If they are positive we will have to focus on building on the combination. Some of those ideas are already beginning to percolate.
Written by: Charles J. Ryan, MD