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Abstract

The androgen receptor (AR) pathway plays a fundamental role in the treatment of prostate cancer, from the localized stage to metastatic disease, even in castration-resistant prostate cancer (CRPC). Despite the significant benefit for the earlier use of second-generation AR pathway inhibitors (ARPI), treatment resistance is still emerging. A deeper understanding of the biology of ARPI resistance is crucial for developing new therapeutic targets. In this review, we will explore the biology of second-generation ARPI resistance and discuss the evolving landscape of third-generation ARPI and steroid hormone inhibitors, which are shaping the future of prostate cancer therapeutics. Targeting the biosynthesis of steroid precursors with CYP11A1 inhibition, inducing AR degradation with proteolysis-targeting chimera degraders or restoring ARPI sensitivity with EZH2 inhibitors are among the most advanced strategies in development. Alongside these new drugs, AR genomic alterations and particularly AR mutations emerge as a promising biomarker for patient selection. These innovative therapeutics help bring more personalized approaches to patients with prostate cancer, aiming to overcome resistance and improve patient outcomes.

Keywords

androgen receptor pathway inhibitor AR alterations AR-targeted therapy castration-resistant prostate cancer drug resistance

Introduction

Targeting the androgen receptor (AR) pathway is the cornerstone of advanced prostate cancer treatment, playing a critical role across a spectrum of disease stages, from locally advanced to metastatic. In the 1940s, Charles Huggins established the oncogenic dependency of prostate cancer cells on androgens, demonstrating tumor regression following surgical castration.¹ However, progression to castration-resistant prostate cancer (CRPC) is nearly inevitable in men with metastatic disease.

Despite resistance to androgen deprivation therapy (ADT), AR signaling persists in CRPC cells, playing a pivotal role in disease progression.^2–5 This insight has guided substantial therapeutic innovations toward overcoming this resistance by persistently targeting the AR in men with CRPC. Notably, second-generation AR pathway inhibitors (ARPI) have dramatically improved outcomes.^6,7 Despite the benefits of second-generation ARPI, resistance ultimately occurs with mechanisms that still rely on AR pathway activation, prompting the need for novel therapeutic developments.

This review aims to offer an overview of the current knowledge on resistance mechanisms to second-generation ARPI and to explore the spectrum of third-generation hormonal agents that are currently under development, with the potential to improve survival of patients with CRPC.

Second-generation AR pathway inhibitors

Even after progressing on ADT, which defines the castration-resistant state, the AR pathway remains the driver of disease progression.^4,8 Understanding the biology of ADT resistance has led to two critical observations:

- The AR pathway is still activated in tumor cells, even with low levels of androgens.^9,10

- Extragonadal androgens maintain the AR pathway activation by providing alternative ligands.^11,12

These observations confirmed the need to enhance the suppression of the AR pathway even after ADT failure and drove the development of second-generation ARPI. Abiraterone acetate, a selective inhibitor of cytochrome P450 17A1 (CYP17A1), inhibits androgen synthesis, while enzalutamide, apalutamide, and darolutamide are AR antagonists that block ligand binding, AR nuclear translocation, AR binding to DNA, and coactivator recruitment.⁴ All second-generation ARPI have demonstrated a survival benefit in patients with CRPC. More recently, doublet or triplet therapies—with docetaxel chemotherapy—have become a new standard of care in metastatic castration-sensitive prostate cancer or even high-risk non-metastatic disease, demonstrating that early intensification of androgen deprivation improves survival without additional major toxicity.⁶

Biology of ARPI resistance

Despite the life-prolonging benefits from second-generation ARPI, the durability of response remains unpredictable, and resistance develops in most patients with metastatic prostate cancer. Similar to ADT resistance, various mechanisms of ARPI resistance are associated with alterations in the AR pathway, including AR genomic aberrations, reprogramming of AR transcriptional activity, and ligand-independent activation.¹³ Concurrently, AR-independent mechanisms of resistance also play a critical role, involving pathways such as PI3K-AKT-mTOR, DNA damage repair, or Wnt-β-catenin.^5,14 Furthermore, selective pressure on the AR pathway may lead to epigenetic reprogramming, conferring a plasticity lineage with stem-cell-like phenotypes or neuroendocrine differentiation.¹⁴ Most studies describing these mechanisms have involved patients treated with ARPI for mCRPC, after ADT alone for mCSPC. It is commonly hypothesized, although not established, that resistance mechanisms are similar when patients are treated upfront with ARPI alongside ADT for mCSPC.

This review focuses on known AR-dependent mechanisms of resistance.

AR genomic aberrations

The AR gene is located on the X chromosome and encodes a steroid transcriptional factor. It consists of four structural domains: the transcriptional domain or N-terminal domain (NTD), the DNA-binding domain (DBD), the hinge region, and the C-terminal domain or ligand-binding domain (LBD).¹⁵ While the NTD is specific to the AR protein, DBD and LBD share homology with other steroid nuclear receptors. Most alterations in the AR gene—such as amplification, splicing variants, and mutations—are observed in the DBD and LBD, altering the protein’s functional activity and “reactivating” the AR pathway. Numerous large-scale tissue and plasma cell-free DNA genomic sequencing studies^5,16–20 have confirmed AR alterations occur during treatment journey in about 60% to 85% of men experiencing failure on ARPI (Figure 1).

Figure 1.

AR-dependent mechanisms of resistance.

AR amplification

AR amplification, resulting in the overexpression of the AR protein, is a compensatory mechanism that enables persistent AR activation with low concentrations of ligands.²¹ AR copy number gain, mostly through tandem duplication,^22,23 occurs in approximately 60% of mCRPC cases. Interestingly, in 10%–15% of patients, amplifications arise from the amplification of the AR upstream enhancer, independent of the AR gene body.²⁴ Additionally, structural truncating rearrangements can occur either concurrently or as a solitary alteration, leading to the production of constitutively active AR variants.²³ This increased sensitivity to low androgen concentration results in resistance to hormone agents. AR copy number gain assessed on circulating tumor DNA (ctDNA) of mCRPC patients is associated with worse outcomes to enzalutamide and abiraterone.²⁵ Despite the prognostic value of AR copy number gain, it has not yet been exploited to guide treatment strategies, and patients with AR amplification continue to receive standard-of-care therapies.

AR splice variants

AR splice variants represent another significant and well-characterized alteration of the AR. Structural gene rearrangements or alternative RNA splicing of intronic sequences generate new variants, with about 20 AR splice variants identified. AR slice variant 7(AR-V7) is the most prevalent in mCRPC and has been extensively studied. AR-V7 encodes an abnormally spliced mRNA isoform, resulting in a protein that lacks the LBD but retains the active transcriptional NTD. Consequently, AR-V7 is constitutively active due to the absence of its LBD.²⁶ The presence of AR-V7 in circulating tumor cells (CTCs) in mCRPC patients is associated with resistance to enzalutamide and abiraterone.²⁷ Though debated,²⁸ AR-V7 may serve as a predictive biomarker for docetaxel treatment strategies.²⁹

AR mutations

AR-LBD gain-of-function somatic mutations (ARm+) are observed in 10% to 25% of mCRPC patients treated with ARPI.^19,30,31 The most frequently identified hotspot mutations are L702H, W742C/L, H875Y, and T878A/S, which confer resistance to ARPI. These missense mutations all occur in the LBD, enabling activation by low-potency androgens and a broader range of non-androgenic steroids, including progesterone, estradiol, DHEA, and glucocorticoids.¹³ T878A and H875Y mutants are activated by progesterone and estrogen, respectively, while L702H is activated by glucocorticoids. This might explain the clinical activity of switching from prednisone to dexamethasone in some patients progressing on abiraterone.³² AR antagonists such as enzalutamide or apalutamide may have an agonistic effect, leading to AR activation when certain mutations are present³³ (T878A, H875Y, F877L), whereas darolutamide inhibits some AR mutations in vitro.³⁴ Although specific AR mutations are associated with in vitro sensitivity to different ARPI, the optimal strategy for selecting ARPI based on AR alterations remains unclear.

Ligand-bypass

The biosynthesis of all steroid hormones is initiated with the conversion of cholesterol into carbon steroids (pregnenolone and subsequently, progesterone) by the CYP11A1 enzyme.³⁵ The next step involves the CYP17A1 enzyme, which converts pregnenolone to dehydroepiandrosterone (DHEA). Adrenal-derived DHEA is then metabolized into dihydrotestosterone (DHT) through various enzymes, including 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, and 5α-reductase. The overexpression of genes encoding steroidogenic enzymes in mCPRC tumor cells facilitates AR activation in a context of low levels of circulating androgens.^12,36 Furthermore, as previously mentioned, the upregulation of steroid precursors might be responsible for the activation of AR mutants.

In the sequence of precursors leading to androgens, corticosteroids play a significant role in the biology of mCRPC. AR-DBD and -LBD share significant homology with other steroid nuclear receptors. This structural similarity enables cross-activation of their respective steroid-responsive transcriptional programs and accounts for the functional overlap observed between AR and the glucocorticoid receptor (GR). Previously, glucocorticoids were proposed as a single agent for the treatment of advanced mCRPC, with modest antitumor activity reported in retrospective studies.³⁵ This effect was likely due in part to the reduction of adrenal androgen synthesis, such as DHEA.³⁷ However, the use of glucocorticoids may also be harmful with an agonistic effect on some AR mutants or with GR overtaking AR activation. It has been shown that AR inhibition leads to GR upregulation in a subset of prostate cancer cells. GR compensates for the activation of AR-targeted genes and thus, GR expression promotes resistance to enzalutamide.³⁸

Post-receptor mechanisms

Despite an improved understanding of AR genomic aberrations, mCRPC cells continue to express and activate full-length, non-altered AR, suggesting that AR-dependent mechanisms may underlie ARPI resistance.³⁹ AR is a transcription factor, working alongside co-regulators such as FOXA1 to bind to specific DNA motifs (androgen response elements, ARE) and promote the expression of AR target genes, such as kallikrein 3 (KLK3); prostate-specific antigen (PSA). In ARPI-resistant mCRPC cells, ARE-independent AR target genes are activated, hijacking the traditional AR-driven programs.⁴⁰ The significance of these non-canonical AR mechanisms in contributing to ARPI resistance has not been fully characterized. However, these findings need to be considered alongside the high frequency of mutations in key co-factors (such as FOXA1 and SPOP) involved in AR-driven transcription.⁴¹ Beyond gene alterations, chromatin accessibility regulated by epigenetics contributes to ARPI resistance. Epigenetic modifiers like EZH2 that affect histone acetylation and methylation are associated with decreased AR signaling and increased epithelial plasticity⁴² and may represent targets for therapy.

Finally, the involvement of AR-independent pathways in ARPI resistance is also undeniably complex and intertwined with AR-dependent resistance. AR signaling continuously interacts with other oncogenic pathways. For example, AR inhibition can activate AKT signaling,⁴³ and the activation of the Wnt/β-catenin pathway can induce resistance to enzalutamide.⁴⁴ This intricate network of interactions highlights the multifaceted nature of resistance mechanisms and underscores the need for comprehensive (and likely, individualized) strategies to overcome ARPI resistance in prostate cancer treatment.

Third-generation ARPI

The understanding of resistance mechanisms has catalyzed the development of third-generation AR pathway inhibitors (Table 1). These novel agents are designed with the goal of inhibiting both the wild-type AR and all emerging variants, including ARm+ and splice variants (Figure 2). This approach represents a significant progress in the effort to overcome the limitations of previous generations of ARPI, which primarily targeted the wild-type AR and were less effective against the diverse array of variants that contribute to resistance in advanced prostate cancer.

Table 1.

Third-generation ARPI: Mechanisms and clinical development.

Mechanism of action	Drugs	Setting	Identifier	Status
CYP11A1 inhibitor	MK-5684/opevesostat	Post-ARPI, post-taxane	CYPIDES (NCT03436485)	Completed
		Post-ARP, post-taxane	OMAHA-003 (NCT06136624)	Ongoing
		Post-ARPI, taxane naïve	OMAHA-004 (NCT06136650)	Ongoing
	ODM209	Post-ARPI, post-taxane	STESIDES (NCT03878823)	Completed
AR degrader/PROTAC	ARV-110/bavdegalutamide	Post-ARPI, post-taxane	ARDENT (NCT03888612)	Completed
	ARV-766	Post-ARPI	NCT05067140	Completed
	BMS-986365	Post-ARPI, post-taxane	NCT04428788	Completed
		Post-ARPI	Recharge (NCT06764485)	Ongoing
	AC-0176	Post-taxane	NCT05241613	Terminated
	HP518	Post-ARPI	NCT05252364	Completed
AR NTD inhibitor	Masofaniten (EPI7386)	ARPI-naive	NCT05075577	Completed
AR splicing inhibitor	Niclosamide	ARPI-naive	NCT02807805	Ongoing
	Cirtuvivint (SM08502)	Post-ARPI	NCT03355066	Completed
AR LBD inhibitor	Proxalutamide (CT-0918)	Post-ARPI	NCT02826772	Completed
	TAS3681/gumelutamide	Post-ARPI	NCT02566772	Completed

Figure 2.

Targeting the androgen receptor pathway.

Steroids biosynthesis blockade

All steroid precursors have the potential to activate the AR, and even more when AR harbors activating mutation. Targeting the entire steroid biosynthesis pathway, beyond focusing only on testosterone and androgens, would be a challenging but attractive strategy.

Opevesostat (ODM-208/MK-5684), is a first-in-class, oral, non-steroidal, selective inhibitor of CYP11A1. This enzyme catalyzes the conversion of cholesterol to pregnenolone, marking the first step of the steroid biosynthesis. Inhibition of CYP11A1 suppresses the production of all steroid hormones, including those involved in the androgen, glucocorticoid, and mineralocorticoid pathways. This broad suppression implies a need for replacement therapy to prevent a clinical adrenal insufficiency-like (AI-like) syndrome. During the lead-in part of the CYPIDES phase I/II trial (NCT03436485), the initial dose to be tested in humans based on animal experience was far too high and associated with such AI-like symptoms. Several lower dose levels were tested before the recommended dose of 5 mg BID was set for further development. Dexamethasone, a potent synthetic glucocorticoid without agonistic effect on the AR pathway,⁴⁵ was finally the chosen agent to prevent AI-like symptoms. Since dexamethasone lacks mineralocorticoid potency, ODM208/MK-5684 is also combined with fludrocortisone (starting dose 100 µg/day). Alternative glucocorticoid regimens were tested but did not improve on the prevention of AI-like events.

Patients eligible for the trial had previously received at least one ARPI and one taxane. In the lead-in part of CYPIDES trial, AR-LBD mutations (ARm+) in ctDNA were not a requirement for participation. A PSA reduction of 50% (PSA50) was achieved in 14 out of 40 (35%) patients. Notably, the efficacy was more pronounced in patients with ARm+, where PSA50 was observed in 71% (12 out of 17) patients compared to only 9% in patients without AR-LBD mutations (ARm-) (p < 0.001).⁴⁶

In the phase II cohort of the CYPIDES trial, patients were screened for ARm+ in ctDNA before enrollment. Among 134 patients included in the trial, 66 harbored an ARm+ at screening. In the ARm+ cohort, half the population were pre-treated with both abiraterone and enzalutamide, with a median PSA above 277 ug/L. In the ARm-cohort, only 34% of patients had received both abiraterone and enzalutamide, with a median baseline PSA above 47 ug/L. Confirming phase I results, a much deeper activity was observed in the ARm+ population: PSA50 was achieved in 55.6% of patients with ARm+ and only 16.7% in those with ARm-.⁴⁷ In ARm+ patients, 42% patients were treated for more than 6 months with a median radiological progression-free survival(rPFS) of 5 months (IQR 2–8 months).

As anticipated, AI-like symptoms were the most common adverse events. Serious AI-like events occurred in 34% of patients in the phase I (mostly when high-dose ODM-208/MK-5684 were used, up to 100 mg BID), underscoring the need for dose adjustment during the lead-in phase. The much lower recommended phase II dose of ODM-208/MK-5684 (5 mg BID) significantly reduced serious AI-like events to only 3% in the phase II study.

Two large randomized phase III trials are currently ongoing: OMAHA-003 (NCT06136624), testing MK-5684 in patients with mCRPC who have failed one prior ARPI and one or two prior taxanes, compared to an alternative ARPI (abiraterone or enzalutamide); and OMAHA-004 (NCT06136650) testing MK-5684 in first-line mCRPC patients who have failed one prior ARPI compared to physician’s choice of second ARPI (abiraterone or enzalutamide). Also, the ongoing umbrella phase I/II study OMAHA-01 is evaluating the combination of MK5684 with Olaparib or taxanes (NCT06353386).

ODM209 was developed alongside ODM208, both CYP11A1 inhibitors. ODM209 was tested in the same setting as ODM208, in patients who experienced disease progression after at least one ARPI and one taxane. Notably, PSA50 was achieved in 47% of patients with ARm+ and 6.7% of those with ARm. The incidence of adrenal insufficiency was comparable to that observed in the phase II trial of opevesostat, confirming a class effect of CYP11A1 inhibitors in the ARm+ population.⁴⁸ Given the progress in ODM208 development, the ODM209 trial has been discontinued.

Androgen receptor degraders

Inducing AR degradation represents an innovative strategy in mCRPC. Proteolysis-targeting chimeras (PROTAC^®) are at the forefront of this approach, offering a novel mechanism to inhibit AR activity. PROTAC degraders are heterobifunctional molecules that bridge an E3 ubiquitin ligase-binding domain to the target protein and degrade the target via the ubiquitin-proteasome system.⁴⁹ Unlike traditional inhibitors, PROTAC degraders also dismantle the scaffolding functions of target proteins and can be recycled to exert an iterative effect, marking a significant advancement in targeted cancer therapy.

ARV-110 (bavdegalutamide) is an orally bioavailable PROTAC AR degrader that bridges AR to cereblon E3 ubiquitin ligase. Preclinical studies have shown that ARV-110 is as effective as enzalutamide in enzalutamide-sensitive models and can inhibit tumor growth in enzalutamide-resistant tumors.⁴⁹ The phase II ARDENT trial (NCT03888612) evaluated ARV-110 in mCRPC patients who were categorized into biomarker-defined subgroups according to their AR-LBD mutation status and chemotherapy treatment history. The results indicated a differential response based on these biomarkers. Among patients harboring ARm+ T878/H875, 46% had PSA declines of at least 50% (PSA50). In contrast, L702H/AR-V7 and ARm-/other AR alterations patients, achieved a PSA50 response in only 4% and 11%, respectively. In the clinically defined subgroup of chemotherapy-naïve mCRPC patients, PSA50% was achieved in 22%.⁵⁰ ARV-110 predominantly caused gastrointestinal side effects. ARV-110 is currently tested in a phase Ib trial in combination with abiraterone in patients with rising PSA on abiraterone (NCT05177042).

ARV-766, a second-generation PROTAC AR degrader, effectively targets a broader spectrum of prevalent and clinically relevant AR-LBD mutations. In a phase I/II trial (NCT05067140), 123 patients with progressive mCRPC after at least one ARPI treatment received ARV-766. Out of the cohort, 53 patients harbored ARm+, over half of the patients had received two prior ARPI, and over half were taxane-pretreated. Among 47 PSA-evaluable patients with ARm+, 43% and 51% achieved a PSA50 and PSA30 response, respectively. Among 20 ARm+ patients with evaluable disease, an unconfirmed response rate was achieved in 30%, including several prolonged responses (>6 months). ARV-766 has a better safety profile compared to ARV-110 with likely less fatigue and gastro-intestinal adverse events.⁵¹ Considering the broader efficacy profile and the better tolerability compared to ARV-110, ARV-766 has been prioritized for phase III development.

BMS-986365 (CC-94676) is another orally administered AR ligand-directed degrader binding the AR to cereblon E3 ubiquitin ligase. The results from the first-in-human study (NCT04428788) shows promising results. Patients with mCRPC progressing after at least one ARPI and one taxane (unless refused or not indicated) were eligible. Out of the 95 patients enrolled, half were previously treated with both abiraterone and enzalutamide, while the other half received taxanes. Overall, 46% of evaluable patients achieved a PSA30 response, with suggestion of a dose-dependent effect for response. Notably, a PSA50 was achieved in 24%, 22%, and 40% in patients with wild-type AR on ctDNA, AR amplifications, and AR mutations, respectively. The median rPFS in the dose expansion part was 6.3 months (95% CI 5.3–10.5), and achieved 16.5 months (95% CI 5.5-NA) in the chemo-naïve population.⁵² The most common adverse events related to treatment were dose-dependent and included asymptomatic QTc prolongation, bradycardia, and fatigue (no grade 3 events occurred). Importantly, events of QTc prolongation and bradycardia resolved with dose reduction. The phase III rechARge trial was recently initiated to compare BMS-986365 with investigator’s choice (docetaxel or an ARPI switch) in patients with mCRPC previously treated with an ARPI (NCT06764485).

Several other AR degraders are under development, targeting men with mCRPC who have experienced disease progression on ARPI, such as HP518 (NCT05252364) and AC-0176 (NCT05241613).

AR N-terminal domain inhibitors

AR non-LBD antagonists represent a novel approach to overcome resistance in prostate cancer treatment by targeting the NTD of the AR protein. This strategy aims to antagonize the AR, regardless of alterations in the C-terminal domain, thereby targeting all AR variants. Many of these variants involve modifications to the LBD that contribute to maintaining AR signaling activity despite conventional therapies.

AR-NTD inhibitors (ANITEN) compounds embody this innovative approach by binding to the NTD and inhibiting its transcriptional activity. However, the initial compounds EPI-002 and EPI506 encountered obstacles related to limited PSA responses and pharmacokinetic issues, notably poor oral bioavailability, which halted their further development.⁵³

Masofaniten (EPI7386), a third-generation ANITEN compound, has been tested both as monotherapy and in combination with enzalutamide. As a monotherapy, masofaniten demonstrated limited efficacy in mCRPC patients who were progressing on standard of care treatments including ARPI and chemotherapy (NCT05075577). In such monotherapy settings, antitumor activity - defined by either PSA response, decrease in ctDNA or radiological shrinkage- was observed in 9 of 31 (29%) patients.⁵⁴ However, preclinical data suggested targeting both the AR-LBD and the AR-NTD could lead to significant differences in AR gene regulation and DNA-damage repair, providing a rationale for combination therapy. Preliminary results from a phase I trial in ARPI-naïve mCRPC patients showed combining masofaniten and enzalutamide resulted in a PSA90 response in 69% of the sixteen evaluable patients, with half of the participants achieving a PSA level of less than 0.2 ng/mL.⁵⁵ The safety profile of this combination was consistent with that of enzalutamide alone, with the addition of gastrointestinal side effects.⁵⁶ Unfortunately, it has been recently announced that the phase II trial randomizing masofaniten with enzalutamide versus enzalutamide alone was terminated after futility analysis.

AR splicing inhibitors

Targeting AR splicing variants emerges as a strategic approach in addressing ARPI resistance and poor outcomes associated with these variants in prostate cancer treatment.²⁷ Despite the moderate results and challenges in recruitment, several drugs have been investigated for their potential to inhibit AR splicing variants.

Niclosamide, an anthelmintic drug, has demonstrated preclinical activity in inhibiting the growth of prostate cancer by targeting the androgen receptor variant 7 (AR-V7). A reformulated version of niclosamide with improved oral bioavailability was tested in combination with abiraterone in men with mCRPC (NCT02807805). Among eight evaluable patients, five achieved a PSA response.⁵⁷ However, further investigation in ARPI-resistant populations is needed as most patients were ARPI-naïve.

The role of alternative splicing in enhancing the coding capacity of genes and its implication in the pathophysiology of numerous diseases like cancers make it a particularly compelling therapeutic target. The spliceosome, a complex involved in RNA splicing, includes families of serine-arginine-rich proteins such as SRPK, CLK, and DYRK, which regulate the phosphorylation of splicing factors.⁵⁸ Cirtuvivint (SM08502), a first-in-class pan CLK/DYRK inhibitor, has shown promise in downregulating alternative splicing. Cirtuvivint achieved a reduction in total CTCs and AR-V7 CTCs in four out of five patients with mCRPC measurable CTCs (NCT03355066). Additionally, early evidence of anti-tumor activity was observed when combined with abiraterone, demonstrating a PSA30 response in half of the patient population (n = 8) who had experienced disease progression on ARPI (NCT05084859).⁵⁹

AR LBD inhibitors

Second-generation AR antagonists (apalutamide, darolutamide, and enzalutamide) target the AR-LBD, effectively inhibiting AR activity in prostate cancer cells. Consequently, alterations in the AR, such as the loss of the LBD or changes in its conformation, can render these drugs ineffective. Novel AR antagonists have been developed to target both the wild-type AR and various AR variants, aiming to overcome these resistance mechanisms.

Proxalutamide (GT0918) is a non-steroidal AR antagonist that exhibits specificity and preclinical activity against T878A mutants. Preliminary results of a phase II trial in mCRPC patients with cancer progression after treatment with an ARPI (either abiraterone or enzalutamide) demonstrated activity, with 15 out of 60 patients achieving stable disease on imaging after at least six cycles of treatment.⁶⁰ Grade 3 and 4 adverse events were rare and reported in 5.3% of patients, including fatigue, transaminitis, and rhabdomyolysis. Early discontinuation due to adverse events such as drug interactions with lipid-lowering medications was noted. Patients previously treated with abiraterone were most likely to achieve durable responses, raising questions about the efficacy of this new drug compared to enzalutamide. In a Chinese open-label randomized phase II trial exploring different doses, 108 ARPI-naïve mCRPC patients were enrolled. The PSA50 response rate was about 23%,⁶¹ with 14% grade 3–4 adverse events.

TAS3681 (gumelutamide) is a next-generation AR antagonist designed to target full-length AR, AR mutants, and AR splice variants. Preclinical data indicated TAS3681 selectively reduced transactivation of both ARm- and ARm+ and downregulated the expression of AR splice variants. TAS3681 was tested in mCPRC patients who experienced cancer progression on treatment with an ARPI (abiraterone or enzalutamide). A confirmed PSA50 response was observed in 4 out of 43 patients (9%), and the overall response rate was about 11%.⁶² The results from the expansion part of the trial, enrolling patients with cancer progression on abiraterone or enzalutamide, are yet to be published (NCT02566772).

While these AR antagonists represent a promising development in the treatment of advanced prostate cancer, their similarity to established second-generation AR antagonists raises questions about their unique position and potential advantages (or limitations) in the therapeutic landscape of the disease. The ongoing challenge is to develop treatments successfully addressing resistance mechanisms while having comparable efficacy on wild-type AR and comparable safety profile to second-generation ARPI.

Glucocorticoid receptor blockade

The GR has increasingly become a focus of attention based on evidence of GR upregulation following ARPI exposure and the potential detrimental effects of corticosteroid therapy in combination with ARPI.⁶³ Consequently, GR modulators were proposed for use in combination with enzalutamide to reverse resistance driven by this alternative nuclear receptor.

Mifepristone, a non-selective steroidal nuclear hormone receptor antagonist, FDA-approved for Cushing Syndrome, was tested in combination with enzalutamide in ARPI-naïve mCRPC patients.⁶⁴ Mifepristone also inhibits CYP2C8 and CYP2C8, enzymes responsible for metabolizing enzalutamide. The drug interactions explained the decreased enzalutamide clearance during the dose-escalation phase. The recommended phase II dose was established as 120 mg of enzalutamide plus 300 mg of mifepristone per day, achieving equivalent drug levels to full-dose enzalutamide monotherapy. In the open-label phase II trial, 66 patients, after a 12-week enzalutamide monotherapy lead-in, were randomized to continue enzalutamide monotherapy or switch to the mifepristone-enzalutamide combination. The study did not meet its primary endpoint of PSA progression-free survival (PFS) (HR of 1.09; p = 0.83), leading to early termination due to lack of efficacy. Given mifepristone’s non-selectivity for steroidal nuclear hormone receptors, including the AR and progesterone receptor, it was hypothesized that mifepristone might have an agonist effect on AR. Additionally, the GR antagonist was added to enzalutamide after 3 months, although GR upregulation might have occurred earlier with enzalutamide exposure. These hypotheses led to studies exploring combinations of enzalutamide with selective GR antagonists like relacorilant (NCT03674814) or exicorilant (NCT03437941).

Both relacolirant (CORT125134) and exicorilant (CORT125281) were tested in combination with enzalutamide in patients progressing on enzalutamide therapy. In the relacolirant study (NCT03674814), 12 patients were evaluable, with 4 out 12 patients achieving a PSA50 response, and a median rPFS was 1.8 months (range 1.7–17.5). Grade 3-related adverse events occurred in 34% of patients, including fatigue and gastro-intestinal disorders. The translational analysis from the exicorilant study confirmed GR overexpression in baseline tumor samples of mCRPC patients resistant to AR antagonist (NCT03437941). Among 25 evaluable patients treated with exicolirant monotherapy, PSA reduction was observed in 4 out 25 (16%) patients, with only one achieving PSA reduction of at least 50%.⁶⁵ To date, no further development of the combination is planned in this setting.

Another selective GR antagonist, ORIC-101, was proposed in combination with enzalutamide in patients with mCRPC progressing on enzalutamide therapy. Among 31 patients treated with the recommended dose, the disease control rate was 25.8% (80%CI: 15.6%–38.5%), which did not meet the pre-specified benefit threshold. No PSA response was observed, and the median PFS was 4.1 months (95% CI: 1.87–NE). The comprehensive molecular characterization performed in this study revealed that the disease control rate was higher in patients without AR nor TP53/Rb1/PTEN alterations, although this did not provide evidence of predictive value.⁶⁶

These studies suggest the intratumoral GR pathway may not be the primary driver of enzalutamide resistance. A neoadjuvant phase II study (NCT05726292) is currently underway, testing relacorilant and enzalutamide in high-risk localized prostate cancer, aiming to gather clinical and biological data to further improve our understanding of GR regulation in conjunction with AR inhibition.

Restoring ARPI sensitivity

As mentioned earlier, post-receptor mechanisms can alter the AR transcriptional activity. Attempts to modulate the AR transcriptional program using histone deacetylase (HDAC) inhibitors have largely been unsuccessful, highlighting the complexity of epigenetic regulation in prostate cancer.⁶⁷ One key epigenetic regulator, EZH2, is upregulated in mCRPC cells and is associated with decreased AR signaling and epithelial plasticity. EZH2 can activate AR gene transcription.⁶⁸ In pre-clinical models, inhibition of EZH2 has been shown to restore the activity of AR antagonists, thus providing a rationale for treatment combination to overcome resistance to AR antagonists.

Tazemetostat and mevrometostat, both selective inhibitors of EZH2, were tested in patients with progressive mCRPC and pre-treated with abiraterone. The CELLO-1 study (NCT04179864) randomized enzalutamide with or without tazemetostat in patients pre-treated with abiraterone and who have not received chemotherapy for mCRPC. The primary endpoint was rPFS by blinded central review and was not statistically reached with a benefit of 2.8 months (HR 0.70; 95%CI 0.32–1.54; p = 0.3704). Interestingly, the median rPFS from the enzalutamide monotherapy arm was longer than historically anticipated,⁶⁹ with a median of 13.8 months.⁷⁰ In the randomized dose-expansion study, patients with a progressive mCRPC pre-treated with abiraterone and no more than one regimen of chemotherapy in any setting were randomized to receive enzalutamide and mevrometostat (NCT03460977) or enzalutamide alone. The primary endpoint was rPFS by investigator. The combination led to a 49% reduction in the risk of progression or death, with an improvement of 8 months in median rPFS (14.3 vs 6.2 months, HR 0.51, 90%CI 0.28–0.95). Patients achieved a PSA50 response in 34.1% and 15.4% in the combination and enzalutamide monotherapy arm, respectively. The most frequent toxicity due to mevrometostat was gastro-intestinal with diarrhea, decrease in appetite, and nausea.⁷¹ Two pivotal phase III studies are ongoing for patients with mCRPC who are pre-treated with abiraterone (MEVPRO-1, NCT06551324) and who are ARPI-naïve (MEVPRO-2, NCT06629779).

Furthermore, overcoming AR upregulation in low-level testosterone environment may be achievable through inducing supraphysiologic levels of androgens. Bipolar androgen therapy (BAT) is based on supraphysiologic testosterone therapy followed by a return to near-castrate serum level over 28 days cycle. The RESTORE phase II study (NCT02090114) evaluated BAT in men with cancer progression on either ARPI (abiraterone or enzalutamide) or ADT alone in mCRPC setting. PSA50 response to BAT was respectively 50%, 29%, and 31% in patients previously treated with enzalutamide, abiraterone, and ADT. Of note, re-exposure to enzalutamide after progression to BAT led to a PSA50 response in approximately 70%, with a median PFS of 4.7 months.⁷² This suggests that BAT may resensitize patients to enzalutamide therapy. BAT may also increase the antitumor immune response and potentially allow for combination with immune checkpoint inhibitors.⁷³

Conclusion and perspectives

Therapeutic advances in metastatic prostate cancer are intricately tied to understanding the complexity of AR pathway, which has led to the development of third-generation ARPI. The promising outcomes from these drugs in early-phase trials leave no doubt about the potential for new therapeutic approaches for patients.

The emergence of new agents directly targeting the AR, including AR-NTD inhibitors and AR degraders, has shown some promising results when used as monotherapies or in combination with second-generation inhibitors. Instead of only demonstrating efficacy, ongoing trials are also exploring their optimal setting in the treatment journey of patients. The monotherapy of these agents may have a modest efficacy after second-generation ARPI treatment, considering the mechanisms of AR-independent resistance. Therefore, combining them with second-generation ARPI to maintain a stronger pressure on the AR pathway could be a preferable option. The expected benefits must be weighed with the toxicity profile, given the excellent tolerance to approved ARPI and the extended durations of therapy. To date, combinations of second-generation ARPI have not shown superiority over monotherapy.⁷⁴

Several ongoing phase III trials evaluating third-generation ARPIs versus either a second-generation ARPI switch or taxane are expected to be pivotal in redefining treatment sequencing. Concurrently, ¹⁷⁷Lutetium-PSMA has received approval for use in chemo-naïve mCRPC patient,⁷⁵ further complicating the therapeutic landscape. The optimal integration of third-generation ARPI within this evolving treatment landscape remains undefined. Many early-phase trials have focused on biomarkers associated with AR genomic alterations, which are linked to a poor prognosis. Among them, AR-LBD mutations have emerged as a promising predictive biomarker of efficacy. However, robust clinical validation in large phase III trials is still underway. A deeper understanding of the prognostic and predictive value of AR-LBD mutations may help refine patient selection and guide personalized treatment strategies in advanced prostate cancer.

In conclusion, these cutting-edge therapies provide renewed hope for patients who have exhausted standard treatments, emphasizing the ongoing importance of targeting the AR, even in the advanced stages of castration-resistant disease.

Footnotes

Acknowledgements

Rebecca Kim is gratefully acknowledged for her English language review. ChatGPT AI assistance was used for improving language and grammar.

Declarations

ORCID iD

Alice Bernard-Tessier

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The future of androgen receptor targeting in prostate cancer: third-generation inhibitors and beyond

Abstract

Keywords

Introduction

Second-generation AR pathway inhibitors

Biology of ARPI resistance

AR genomic aberrations

AR amplification

AR splice variants

AR mutations

Ligand-bypass

Post-receptor mechanisms

Third-generation ARPI

Steroids biosynthesis blockade

Androgen receptor degraders

AR N-terminal domain inhibitors

AR splicing inhibitors

AR LBD inhibitors

Glucocorticoid receptor blockade

Restoring ARPI sensitivity

Conclusion and perspectives

Footnotes

Acknowledgements

Declarations

ORCID iD

References