Novel Strategies Aimed at Overcoming Resistance to AR Therapy in Prostate Cancer

Emmanuel S. Antonarakis, MBBCh

The last decade has witnessed a leap forward in the treatment of the challenging castration-resistant form of prostate cancer (CRPC), following the discovery that targeting the androgen receptor (AR) remains a viable strategy in this advanced form of disease. In spite of this, CRPC remains incurable, with most patients developing resistance to currently available AR-targeting therapies.

With increased understanding of the biology of CRPC and the mechanisms of action of AR-targeting drugs, researchers are developing a growing appreciation for the extensive heterogeneity and complexity of both prostate cancer and androgen signaling.

Androgen Receptor Targeting and Resistance

This figure illustrates the complexities of androgen receptor signaling in prostate cancer and some of the agents used to target activity.

3βHSD1 indicates 3β-hydroxysteroid dehydrogenase type 1; AR, androgen receptor; C, C terminal of DBD; CYP17, cytochrome P450 17; DBD, DNA binding domain; DHEA, dihydroepiandrosterone; DHT, dihydrosterone; GR, glucocorticoid receptor; N, N terminal of DBD; PSA, prostate-specific antigen; T, testosterone.

Adapted from Stein MN, Patel N, Bershadskiy A, et al. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer. Asian J Androl. 2014;16(3):387-400.

By applying clinical trial experience with AR-targeting agents, the field is attempting to stay one step ahead of this resilient foe by trying new combinations and developing new drugs to overcome resistance while searching for biomarkers to help guide treatment decision making (Table 1).

Table 1. Novel Agents to Overcome AR Resistance in Active Clinical Trials

*Trial is ongoing, but not recruiting participants.

AR indicates androgen receptor; CRPC, castration-resistant prostate cancer; CYP17A, cytochrome P450 17A enzyme; mCRCP, metastatic castration-resistant prostate cancer.

Understanding of AR Signaling Evolves

In recent years, comprehensive genomic profiling studies have pinned down four major signaling pathways involved in the development and progression of prostate cancer, but more than 70 years ago the Nobel Prize-winning findings of Charles B. Huggins and colleagues had already intimately linked one of these pathways to prostate cancer.

That was the pathway regulated by the androgen receptor, a member of the nuclear steroid hormone family that acts as a DNA-binding transcription factor and plays a major role in normal prostate function. Residing in an inactive form in the cytoplasm, ARs move into the nucleus upon binding of androgens and stimulate transcription of genes involved in cell cycle regulation, growth, and survival. In prostate cancer, increased levels of circulating androgens promote AR signaling and aberrant activation of these cellular processes.

The importance of the AR pathway in prostate cancer has driven the clinical development of therapies designed to reduce the levels of androgens or to block the AR signaling network. This began with androgen deprivation therapy (ADT), primarily achieved through surgical intervention or chemical castration (agonists and antagonists of gonadotropin-releasing hormone, which regulates testosterone synthesis). Neither surgical nor chemical castration is completely effective at reducing circulating androgen levels, and patients inevitably progress to more aggressive and ultimately fatal CRPC, in which the cancer continues to grow despite the low androgen environment. Researchers turned to targeting the AR to block the body’s ability to use androgens, to complement the use of ADT, and to induce maximal androgen blockade. The first generation of AR antagonists were highly effective, but eventually developed agonist activity, especially in the presence of high levels of AR, and were ineffective in CRPC.

CRPC: A Major Therapeutic Challenge

Originally, CRPC was believed to have evolved to become androgen-independent, driving unresponsiveness to ADT and antiandrogens and limiting their utility in CRPC.

During the past decade, a significant paradigm shift has occurred following revelations of the continued critical role of the AR in CRPC progression.

AR signaling has again become the prime focus for therapeutic intervention, prompting clinical development of two different classes of antiandrogen therapy: (1) second-generation, more potent, pure antagonists of AR; and (2) inhibitors of androgen biosynthesis. Intensive research efforts culminated in FDA approval of two novel AR-targeting agents in recent years.

Enzalutamide, an AR antagonist, was approved in 2012 as a treatment for patients with metastatic CRPC who have previously received docetaxel. Abiraterone, approved in combination with prednisone in 2011, inhibits the cytochrome P450 17 alpha (CYP17A) enzyme that is essential for androgen synthesis.

Both agents demonstrated a survival advantage in phase III trials in patients with CRPC in both the pre- and post-chemotherapy settings and have rapidly entered routine clinical practice. While they have revolutionized CRPC treatment, responses are short-lived and all patients ultimately relapse.

AR-V7 Variant May Serve as Biomarker

Given the likely role of AR signaling as “master regulator” of prostate cancer, it is unsurprising that a significant limitation of drugs targeting this pathway is the development of resistance. Prostate tumors rapidly evolve many different mechanisms of resistance and these are currently stymying efforts to effectively attack the malignancy through AR signaling.

A central mechanism of resistance is persistent activation of the AR. This can be achieved through alterations in its structure, including mutations, most commonly in the ligand-binding domain, or the formation of splice variants. AR splice variants, which occur in around one-third of patients with CRPC, are currently one of the best characterized resistance mechanisms. In particular, the formation of the AR-V7 variant has been the subject of significant attention. This variant, and many of the others characterized to date, encode receptors lacking the C-terminal domain, which contains the ligand-binding portion.

Emmanuel S. Antonarakis, MBBCh, assistant professor at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, and colleagues examined whether the presence of AR-V7 in the circulating tumor cells of 31 patients treated with abiraterone and 31 treated with enzalutamide was associated with resistance. AR-V7 was detectable in 39% and 19% of patients, respectively, and these patients had lower prostate-specific antigen (PSA) response rates and shorter rates of PSA progression-free survival (PFS), clinical or radiographic PFS, and overall survival (OS).

AR-V7 may prove useful in predicting upfront resistance to AR-targeted therapy and could potentially be used to help guide therapeutic decision making. Interestingly, another recent study showed that AR-V7 is not associated with resistance to taxane chemotherapy, leading the authors to speculate that AR-V7—positive patients should be offered chemotherapy rather than hormone therapy for the treatment of metastatic CRPC.

Though the results of these trials are striking, there is still some way to go before this methodology could be applied to clinical decision making.

Many Mechanisms of Resistance

It is becoming increasingly clear that there are likely to be many different mechanisms of resis- tance to AR-targeting in prostate cancer, several of which may coexist in the same patient (Table 2).

Table 2. Potential Mechanisms of Resistance to AR-Targeting in Prostate Cancer

AR indicates androgen receptor; CYP17A, cytochrome P450 17 alpha; DHT, dihydrosterone; HSP, heat-shock protein; LBD, ligand binding domain.

One important mechanism of resistance is activation of the AR by noncanonical ligands, commonly achieved through AR mutations (eg, T877A, shown to enable AR activation via progesterone and other ligands). The AR can also be activated by growth factors and cytokines to promote resistance, by steroid precursors upstream of CYP17A, and even by exogenous corticosteroids.

The latter have important implications for the use of CYP17A inhibitors like abiraterone. CYP17A catalyzes two steroid reactions and has both 17a hydroxylase activity and 17,20 lyase activity. Inhibition of hydroxylase activity inhibits cortisol synthesis, which leads to increased levels of adrenocorticotropic hormone (ACTH).

Preclinical studies have suggested that high ACTH levels drive a feedback loop that increases the levels of hormones upstream of CYP17 and can fuel a “backdoor” pathway of androgen synthesis, thus activating a promiscuous AR. Abiraterone is adminis- tered with the corticosteroid prednisone to increase cortisol levels and prevent increased ACTH, but it has been shown that these exogenous corticosteroids may activate a mutant AR that drives resistance.

Prostate tumors have also developed the ability to synthesize their own androgens from cholesterol and to make more efficient use of the low level of residual androgens found in the circulation after treatment, in order to overcome the low androgen environment. Both of these mechanisms have been shown to require the enzyme 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which converts dihydroepiandrosterone (DHEA) into the potent androgen dihydrosterone (DHT) that can then activate the AR.

A gain-of-function mutation in this enzyme (367T) was recently described, which prevents the degradation of 3βHSD1 and thus increases its availability for androgen biosynthesis.

It was initially hoped that it would be possible to sequence enzalutamide and abiraterone, so that when resistance to one occurred the other agent could be employed. Unfortunately, numerous studies have shown that response rates are significantly diminished in progressing patients who receive the alternative agent, compared with upfront responses. This suggests that there may be significant cross-resistance between the two agents and that resistance to one drug may, at least in some cases, imply resistance to the other. There have also been reports of cross-resistance between both agents and the chemotherapy drug docetaxel.

Cross-resistance has important implications for therapeutic decision-making. Robert Dreicer, MD, MS, deputy director at the University of Virginia Cancer Center, pointed out during a presentation at the 8th Annual Interdisciplinary Prostate Cancer Congress® and Other Malignancies in New York City in March that it is difficult to advocate routine sequential use of abiraterone and enzalutamide in a symptomatic patient when there is a relatively high likelihood of a poor response.

Staying One Step Ahead

Treatment Strategies

Researchers are striving to meet the challenge of CRPC and to stay one step ahead of the disease in a number of different ways. To address the issue of cross-resistance, several ongoing studies are designed to evaluate the optimal sequence of current prostate cancer therapies, including:

• PRIMCAB—A phase II study comparing cabazitaxel with AR-targeted therapy in patients with chemotherapy-naïve metastatic CRPC who have primary resistance to abiraterone or enzalutamide (NCT02379390)
• ALLIANCE—A phase III trial comparing enzalutamide monotherapy to enzalutamide in combination with abiraterone and prednisone in patients with chemotherapy-naïve metastatic CRPC (NCT01949337)
• STAMPEDE—A phase II/III trial assessing whether five treatments that are usually used after hormone therapy has failed would be more effective if administered earlier in the course of the disease in combination with ADT. The drugs being tested in the nine-arm trial are: zoledronic acid, docetaxel, celecoxib, abiraterone, and enzalutamide.

Novel Agents

A significant number of novel agents that would attack resistance mechanisms to AR therapies are currently undergoing preclinical evaluation, and several are also being tested in clinical trials.

Among them are next-generation, more potent AR antagonists, such as ARN-509 and ODM-201, and more selective CYP17A inhibitors that target lyase activity but not hydroxylase activity. The latter are highly sought after for their proposed ability to decrease production of androgens while maintaining cortisol levels, thereby reducing the ACTH-induced feedback loop that activates the AR.

One such inhibitor, orteronel (TAK-700), demonstrated significant antitumor activity in two phase III trials in patients with metastatic CRPC: ELM PC-4 in chemotherapy-naïve patients, and ELM PC-5 in the post-docetaxel setting. However, neither study met the primary endpoint of improved OS, and the Takeda Pharmaceutical Company announced in June 2014 that the development program for the drug would be terminated.

Based on the hypothesis that combined inhibition of androgen biosynthesis and AR antagonism may result in more complete blockade of AR signaling, several dual inhibitors are being evaluated.

VT-464 is the most recent offering and, in addition to being a dual inhibitor, it also effectively targets several AR variants (F876L and T877A, associated with enzalutamide and abiraterone resistance, respectively). Preliminary results of a phase I/II study were reported at the 2015 Genitourinary Cancers Symposium. The drug was well tolerated, with no mineralocorticoid excess syndrome observed even though no supplemental steroids were used, and there was a PSA90% response in one patient previously treated with enzalutamide.

Finally, a number of strategies for targeting areas of the AR outside the ligand-binding domain are also being investigated as these could effectively inhibit AR splice variants that lack this domain. The most attention, thus far, has been placed on the N-terminal domain, which represents a significant challenge due to its intrinsically unstructured nature.

Agents targeting this domain include EPI-506 from Essa Pharma Inc. In March, Essa filed an investigational new drug application with the FDA in order to bring EPI-506 into clinical trials.

Key Research

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