Targeting the Androgen Receptor Pathway in Prostate Cancer: A PROTrACted Struggle

SUMMARY

The Androgen Receptor (AR) is the most important therapeutic target for metastatic prostate cancer. Though clinical responses to AR inhibition are nearly universal, so is progression, usually accompanied by reactivation of AR signaling. A new small molecule dual AR degrader/inhibitor shows promise in overcoming resistance and improving clinical outcomes.

COMMENTARY

In this issue of Clinical Cancer Research, Nayak and colleagues (1) present preclinical and clinical evidence that a novel Androgen Receptor (AR) Ligand-Dependent Degrader (LDD), can suppress the growth of prostate cancers that are resistant to current AR-targeting therapies. This is an important advance, as the campaign to eradicate AR activity in metastatic prostate cancer (mPC) has been ongoing since the foundational work of Huggins and colleagues who reported, over 80 years ago, that reducing testosterone resulted in dramatic clinical responses in men with mPC (2). Since then, Androgen Deprivation Therapy (ADT) has been the cornerstone of treatment for mPC. ADT initially took the form of surgical castration and synthetic estrogen treatments to suppress the production of testosterone and DHT, the primary AR ligands. In the 1980s, ADT evolved with the development of LHRH analogs that suppressed testosterone levels by blocking hormone signaling from the pituitary to the testis. Approaches to directly inhibit androgen binding to the AR arrived in the 1990s with small molecule antagonists of the AR entering clinical practice followed by more potent second-generation AR inhibitors in the 2010s. Alongside these agents, CYP17 inhibition was added to treatment regimens to prevent adrenal and intratumoral androgen synthesis and together with AR antagonists are termed AR pathway inhibitors (ARPIs) or AR signaling inhibitors (ARSI). The development of ever more stringent and sophisticated approaches to disrupt AR function was driven by the recognition that tumors continue to evolve to reactivate AR signaling and inevitably progress to castration-resistant mPC (CRPC). Despite intense therapeutic pressure resulting from combinations of agents designed to repress AR signaling, resistant tumors usually recur with evidence of AR activity (Figure 1).

Figure 1. The Protracted struggle to target AR activity in prostate cancer.

(A) The vast majority of newly diagnosed metastatic prostate cancers are driven by androgen receptor (AR) activity (ARPC) and respond to treatments that deprive tumors of circulating androgens (ADT). Following responses to ADT, metastatic castration sensitive prostate cancers (mCSPC) commonly progress to castration resistant prostate cancer (mCRPC) which is accompanied by reactivation of AR signaling. mCRPC responds to further AR targeting using AR signaling inhibitors (ARSI). Progression on ARSI therapy is also usually accompanied by reactivated AR signaling. Mechanisms of ADT and ARSI resistance include AR mutations, amplification of the AR locus, generation of intratumoral androgens, and AR splice variants (ARsv), each of which promote AR signaling. AR degraders (AR-D) have the potential to overcome mCRPC progression driven by persistent AR pathway activity. (B) Current practice for treating newly diagnosed mCSPC involves combining ADT and ARSI therapy to more effectively repress AR signaling. AR-Ds may produce deeper clinical responses when administered earlier in the disease course. Resistance pathways may involve the development of AR-null tumors via epigenetic reprogramming to alternative lineages such as neuroendocrine prostate cancer (ARPC).

The mechanisms of progression to CRPC are diverse. The AR can acquire mutations in the ligand binding domain (LBD) of the protein to allow promiscuous activation by a diverse set of hormone ligands, like progesterone, or convert AR antagonists into AR-agonists. Similarly, AR gene/enhancer amplification increases AR expression, enhances sensitivity to low ligand levels, and converts first-generation AR antagonists into weak agonists. The AR can also be truncated to a constitutively active form through alternative splicing or gene rearrangements. Notably, these AR splice variants generally lack the LBD and consequently lose binding sites for AR antagonists – thus promoting resistance. Intratumoral androgen synthesis can bypass the suppression of testicular androgen production. Ultimately, most CRPC tumors that are refractory to ADT and ARSI treatment, continue to demonstrate AR activity, and until proven otherwise remain dependent on AR signaling, highlighting the need for more effective modalities capable of completely ablating AR-function.

The invention Proteolysis Targeting Chimera drugs (PROTACs), a type of Targeted Protein Degrader (TPD), represents a promising new avenue to target previously undruggable proteins as well as more effectively suppress existing drug targets. PROTACs are heterobifunctional small molecules that join a target protein, like AR, to a E3 ligase to facilitate ubiquitination and proteasomal degradation of the target. Since the first report of PROTACs degrading hormone receptors over 20 years ago (3), the field has advanced to clinical-stage investigational drugs forecasted to be approved for use within the next few years. Dozens of clinical trials are ongoing for oncology and inflammation targets like AR, ER, KRAS, BRAF, BTK, and IRAK4. These initial entrants made use of existing binders to proteins like KRAS and AR that are insufficiently impaired by pure inhibitors due to mechanisms that range from reduced negative feedback signals that result in pathway reactivation, or increased target expression. Future possibilities for PROTACs may expand to include non-enzymatic proteins, scaffolding functions of enzymatic proteins, tissue selective drug activity through an expanded repertoire of E3 ligase binders, and antigen-mediated targeting using antibody conjugation.

The work of Nayak and colleagues now advances a PROTAC drug, BMS-986365 into the clinic as a therapeutic for mCRPC (1). The experiments included in vitro data that validates the mechanism of action of BMS-986365 as specifically degrading the AR in a ligand-binding and proteosome-dependent manner. BMS-986365 also exhibited superior in vivo suppression of CRPC xenograft models compared to enzalutamide, a potent ARSI. Finally, a patient that had progressed on enzalutamide treatment is shown to have a PSA and radiographic response to BMS-986365.

BMS-986365 is one of the most advanced PROTACs in clinical development. A phase 3 clinical trial, rechARge (CA071–1000, NCT06764485) is enrolling patients with CRPC that have failed prior treatment with an ARPI. The efficacy of the drug will be compared to a second ARPI or docetaxel, with radiographic progression-free survival (rPFS) as the primary endpoint and overall response rate and PSA response rate as secondary endpoints. Given the high degree of cross resistance of ARPIs, the results of this trial will be a test of whether more effective suppression of AR activity will improve outcomes. In a safety and dose-finding phase I trial of BMS-986365 (CC-94676-PCA-001, NCT04428788), the median rPFS in heavily pretreated CRPC patients was 8.3 months in the highest dose cohort, suggesting a subset of patients may benefit (4).

The deep molecular characterization of patients treated with AR degraders such as BMS-986365 will be important and informative. High levels of the AR due to amplification of the AR genomic locus in patients treated with ADT and ARSIs may challenge the ability of ligand dependent degraders to completely eliminate AR protein, as will the presence of AR splice variants that lack binding sites for the current generation of AR-targeting PROTACs. Consequently, one resistance scenario is tumor progression with evidence of continued AR activity (Figure 1). Alternatively, with AR repression, prostate cancers exhibit the remarkable ability to undergo transdifferentiation accompanied by uncoupling from AR dependence, and progression may occur via the emergence of AR-null tumors including neuroendocrine and double-negative phenotypes (5) (Figure 1B). Notably, if AR degraders demonstrate clinical benefit in CRPC, the development pathway will likely follow previous success in applying combination treatments earlier in the disease course – for example at the initial diagnosis of hormone sensitive disease, where potent eradication of AR signaling may be easier to achieve, with the potential for durable long-term disease control.