First, a quick review of the history of targeting the AR (all dates approximate):
1. 1940’s: Orchiectomy shows clinical benefit for men with metastatic disease.
2. 1960’s: LHRH effectively targeted to produce castration.
3. 1970-80’s: Estrogens and steroidal anti-androgens initiated, moderate efficacy.
4. 1990-2000’s: Anti-androgen withdrawal responses described, androgen receptor amplification discovered as a root cause of this phenomenon – apalutamide and enzalutamide developed as a means to target this.
5. 2006-2019: Pivotal clinical trials demonstrate that next-generation AR targeted drugs demonstrate high rates of response, progression-free survival (PFS) and overall survival (OS) advantages, worldwide regulatory approvals follow.
6. 2017-2020: Benefits of early AR targeting in metastatic castration sensitive disease and non-metastatic castration-resistant prostate cancer (nmCRPC) are revealed with LATITUDE, ENZAMET, and ARAMIS.
This is an almost 80-year history of successfully treating disease through this modality, and one of the oldest and most successful treatment paradigms in cancer therapy. But the reality is, when we use these therapies over the long haul, resistance always seems to develop.
How will we overcome this? Here are a few potential thoughts.
1. Design better AR inhibitors?
There are a few other AR inhibitors emerging from labs around the world, and it is within the realm of the possibility that we could develop another therapy that is more potent than enzalutamide or apalutamide, but what would that look like? “Potency” of a drug is an interesting term, essentially it pertains to the amount of drug (e.g. milligrams) that are needed to inhibit the receptor in vitro. Yet, is that really the problem we need to address? Potency is not really the reason these drugs fail to work over time. Greater potency could perhaps lead to a higher PSA90 or prostate-specific antigen complete response [PSA CR] (patients who experience a 90% decline in PSA on therapy or a complete PSA response). This could be a step forward because we know from past experiences that patients with these deeper PSA responses go longer on therapy and live longer. If we could push the proportion of patients who have a PSA90 or PSA CR beyond the 25-30% we see, that might be beneficial. A key to this is that we may observe the greater potency of these therapies relatively early. A more potent AR inhibitor would lead to fast and deep PSA declines.
Another definition of 'better' is the possibility that we could improve the long term tolerability of AR inhibitors even if we don’t improve their efficacy. Although relatively few patients discontinue outright their AR inhibitors due to adverse effects, some do. One approach underway that I am proud to be part of is an upcoming head to head comparison of enzalutamide to darolutamide based on the possibility that darolutamide is less likely to penetrate the central nervous system (CNS) and thus, have fewer cognitive and fatigue side effects. As long as efficacy is not compromised, an AR drug that does not penetrate the brain would most likely be 'better'. We shall see.
2. Develop AR degraders?
Ever since I have been studying the AR there has been talk about small molecules that can degrade the androgen receptor. Typically this involves enzymatic degraders that are chemically tagged to a molecule that gets them bound to something (eg. VHL) and enabling proteolysis. The chemistry is elegant behind some of these small-molecule proteolysis targeting chimera (PROTAC) AR degraders, but we have yet to see convincing clinical data. My hunch is that a) it is hard to preserve this chemistry in vivo and/or b) we will see that such approaches have a narrow therapeutic index, and the benefit to toxicity ratio is not favorable. Yet, it’s a start, degrading the AR (as long as we can confine that degradation to occurring only within cancer cells!) would be a good thing.
3. Target the mechanisms of resistance?
Many papers have been written on the pathways and processes that get activated in enzalutamide-resistant cell lines that include truncation of the AR and altogether different processes. One approach that has struggled to find traction is the pharmacologic inhibition of the AR-DNA binding domain – effectively eliminating the binding of the androgen receptor to the DNA regions that are activated by the receptor. This approach is attractive if the ARV7 splice variant is a key driver of CRPC disease progression, but we are not sure that it is. One mechanism, upregulation of CREB5, an AR activator molecule, has recently been described1. Through its upregulation amidst the treatment stress of enzalutamide treatment in vitro CREB5 supports the retention of the AR on DNA and the stable recruitment of co-activating molecules. If it could be targeted it could be employed at the time of its upregulation (e.g. at enzalutamide resistance) or potentially in combination with AR antagonists. More to follow on this.
4. Partner AR inhibition by blocking something else
When targeting the AR we are asking a lot of one small molecule. Prostate cancer growing in a human host is a complicated biological milieu and it is remarkable that we get as much clinical efficacy as we do out of them. When we inhibit the AR, a whole host of known and unknown biological events are initiated, some of which may already be druggable. One that is within reach is the potential for combination with poly-ADP-ribose polymerase (PARP) inhibitors. The androgen receptor is a key part of maintaining a robust DNA repair network within prostate cancer cells. It is hypothesized that AR inhibition, through a blockade of the AR-related DNA repair. We have already seen some compelling results with the combination of abiraterone with olaparib from Noel Clarke and the PROpel study is underway to demonstrate whether this combination can be of use to patients both with and without DNA repair defects.
The PROpel design (abiraterone vs abiraterone plus olaparib in CRPC) is indeed compelling, but I have wondered if it may fall short due to the fact that abiraterone is not a direct AR inhibitor (it inhibits androgen production), and this may result in a lesser effect on the upregulation of PARP that is the target of the olaparib. It may be that enzalutamide or another direct antagonist may be more effective in inhibiting AR-supported DNA repair. As an alternative approach, we in the Alliance for Clinical Trials in Oncology will be conducting CASPAR, a Phase III trial of co-inhibition of androgen signaling and PARP as a novel therapy in previously-untreated metastatic CRPC. This is a study of enzalutamide with and without rucaparib. This Phase III placebo-controlled study, like PROpel, will include patients both with and without DNA repair mutations. If PROpel fails to confirm the benefit that seemed apparent in the Phase II experience, and CASPAR is positive, it will affirm the relationship of the AR and DNA repair signaled through PARP.
5. Alter the timing and sequence of the therapy to use it more sparingly
Finally, one concept potentially worth considering is to alleviate the treatment mediated stress on the androgen receptor, perhaps through intermittent therapy, in order to prevent or delay progression. Most of the in vitro studies, such as the CREB5 study detailed above, demonstrate the upregulation of these various mechanisms resulting from continuous and potent AR antagonism. Could we delay this if we inhibited the AR intermittently? This might be worth a little pre-clinical work. One of the challenges clinician-researchers face in this regard is how to tease out an effect in patients in a Phase II study. Sure, a Phase III randomized trial will answer this, but that will take 5 years, over 1000 patients and a lot of money. Getting a hint of this in a small population Phase II study is another question altogether.
We have made a lot of progress targeting this molecule. Is that work done? Probably not.
Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Director and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota
Published Date: February 5th, 2020
1. Hwang, Justin H., Ji-Heui Seo, Michael L. Beshiri, Stephanie Wankowicz, David Liu, Alexander Cheung, and Ji Li et al. 2019. "CREB5 Promotes Resistance To Androgen-Receptor Antagonists And Androgen Deprivation In Prostate Cancer". Cell Reports 29 (8): 2355-2370.e6. doi:10.1016/j.celrep.2019.10.068.