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. 2025 Sep 18;35(6):696–706. doi: 10.1097/MOU.0000000000001341

Toxicities of novel androgen receptor pathway inhibitor targeted therapies in advanced prostate cancer

Romain Iaxx a, Diego Teyssonneau a,b, Catherine Fallaha a,c, Virginie Grouthier d, Guilhem Roubaud a
PMCID: PMC12517708  PMID: 40970404

Abstract

Purpose of review

Advanced prostate cancer (PCa) is still dependent on the androgen receptor (AR) pathway, which has led to the development of new compounds – beyond androgen receptor pathway inhibitors (ARPIs) currently used in clinical practice – and that are able to overcome acquired resistance through AR mutations, splice variants or amplifications. With these new drugs, novel toxicities occur with new challenges for both patients and physicians. This narrative review aims to report and discuss emergent and/or related adverse events associated with these new hormonal therapies.

Recent findings

Adrenal insufficiency-like events and cardiac disorders were the main specific adverse events associated with these new hormonal therapies for advanced PCa. Different profiles of toxicities were also related to either combination of these drugs with usual ARPIs or to compounds with multiple effects on AR pathway, mainly AR antagonism.

Summary

As these new treatments are still under development, physicians need to keep up-to-date with potential emerging toxicities and manage acute and long-term toxicities.

Keywords: androgen receptor degrader, androgen receptor ligand-binding domain mutations, androgen receptor pathway inhibitors, androgen receptor splice variants, toxicity

INTRODUCTION

With approximatively 1 275 000 new cases every year, prostate cancer (PCa) is the second most common cancer for men worldwide, leading to 360 000 deaths each year despite major therapeutic advances [1]. PCa initiation and growth is androgen-dependent [2] providing the rationale for androgen deprivation therapy (ADT) as first treatment in patients with advanced PCa. Even though ADT can reduce total testosterone levels in the blood to under 50 ng/dl, PCa under ADT can still progress, developing castration resistance. This is mainly because the androgen receptor (AR) pathway can be activated independently of androgens [3,4]. This finding has led to the development of new AR antagonists, known as androgen receptor pathway inhibitors (ARPIs) [5]. Combination of these ARPIs (e.g. abiraterone acetate + prednisone or apalutamide or darolutamide or enzalutamide) with ADT has demonstrated a survival improvement and ARPI+ADT is now a standard of care in both hormone-sensitive and castration-resistant settings [5,6]. However, resistance still continues to emerge with several AR-related mechanisms, such as AR point mutations in the ligand-binding domain (LBD), AR alternative splicing variants (AR-V or AR-SV), or AR amplification or overexpression [7,8]. New drugs of different pharmacological classes are currently under development to overcome these resistance mechanisms. While some promising results have been reported in terms of antitumoral efficacy [9▪▪], these new compounds expose patients and physicians to emergent adverse events to manage.

This narrative review aims to describe toxicities of novel ARPI-targeted therapies that may soon become part of the therapeutic landscape. 

Box 1.

Box 1

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MATERIALS AND METHODS

We carried out a comprehensive literature search on PubMed for articles and abstracts from the major clinical oncology conferences, published in English, to identify studies investigating drugs of interest. We limited our search to on early clinical trial data published and/or communicated between January 2010 and December 2024. Molecules for which only preclinical data were available were excluded. Reference list of the identified literature was further explored and evaluated for relevance.

RESULTS

Serious adverse event (SAE) and/or grade at least 3 adverse events of novel ARPI targeted therapies are summarized in Table 1 and described in more detail below. The antitumoral activities of different compounds on the AR pathway are illustrated in Fig. 1.

Table 1.

Toxicity of different new drugs targeting the androgen receptor pathway

Mechanism of action Drug Specificity Design PMID n Population Associated drug (excepted ADT) Primary endpoint DLT/MTD SAE and/or grade ≥ 3 toxicity Frequency (%) AE classification DDI
Androgen biosynthesis inhibitors ODM-208 CYP11A1 inhibitor phase 1 38320513 47 mCRPC post ARPI and post chemo 0 safety; define DMT 1 DLT (adrenal insufficiency): 50 mg BID adrenal insufficiency 31.9 NCI CTCAE (v4.03) 0
anemia 14.9
hyponatremia 12.8
hypertension 10.6
pulmonary embolism 10.6
tumor pain 8.5
amylase increased 8.5
lipase increased 6.4
ALP increased 6.4
CPK increased 4.3
asthenia 4.3
ALT/AST increased 2.1
hyperkaliemia 2.1
bone pain 2.1
diarrhea 2.1
abdominal pain 2.1
constipation 2.1
hypokalemia 2.1
phase 2 45 mCRPC post ARPI and post chemo; with AR mutation 0 safety; preliminary efficacy NA anemia 13.3
adrenal insufficiency 6.7
hypertension 6.7
pulmonary embolism 6.7
tumor pain 6.7
ALP increased 6.7
fatigue 6.7
asthenia 4.4
bone pain 4.4
diarrhea 4.4
dyspnea 4.4
back pain 4.4
hypotension 4.4
hyponatremia 4.4
amylase increased 2.2
lipase increased 2.2
hyperkaliemia 2.2
hyperkaliemia 2.2
muscle spasms 2.2
arthralgia 2.2
decreased appetite 2.2
urinary tract infection 2.2
Galeterone CYP 17 inhibitor, AR antagonist and AR degrader phase 1 26527750 49 m0CRPC or mCRPC; chemo and ARPI naive 0 safety; define DMT and RP2D Not reported ALT increased 16.3 NCI CTCAE (v4.0) 0
AST increased 6.1
bilirubin increased 2
fatigue 2
phase 2 28 m0CRPC or mCRPC chemo and enza-naive (abiretone authorized) 0 pharmacokinetic; safety and efficacy No DLT observed ALT increased 10.7
AST increased 3.6
constipation 3.6
diarrhea 3.6
rash 3.6
phase 3 31542304 19 mCRPC chemo and ARPI naive; AR-V7 + 0 screen and characterize AR-V7+ mCRPC, efficacy NA anemia 11 not reported 0
fatigue 5
hepatic failure 5
Novel AR antagonist HC-1119 deuterated form of enzalutamide phase 1 (dose escalation) 34109624 24 mCRPC ARPI naive (post chemo authorized) 0 safety, PK, DLT and PD No DLT observed; MTD not reached hypertension 6 NCI CTCAE (v4.03) 0
anemia 6
phase 1 (dose expansion) 19 0 PSA response Not reported hypertension 5
neutropenia 5
proteinuria 5
SHR3680 AR antagonist with low brain distribution phase 1/2 35241087 197 mCRPC post chemo; ARPI naive 0 phase 1: safety. Phase 2: PSA response rate No DLT observed; MTD not reached leucopenia 1.5 NCI CTCAE (v4.03) 0
neutrophil count decreased 1
hypertension 1
hypertriglyceridemia 0.5
decreased appetite 0.5
elevated ALT 0.5
gynecomastia 0.5
anemia 0.5
GT0918 = proxalutamide AR antagonist with higher affinity than enzalutamide phase 1 32460179 16 mCRPC post chemo +/- post ARPI 0 safety, PK and anti tumor efficacy No DLT observed; MTD not reached 0 not reported NCI CTCAE (v4.0) 0
phase 2 36919366 108 mCRPC ARPI naive (post chemo authorized) 0 PSA response rate NA anemia 2.8 NCI CTCAE (v4.0) 0
decreased appetite 1.9
fatigue 1.9
hypertension 1.9
weight loss 0.9
hypertriglyceridemia 0.9
hypokalemia 0.9
hypophosphatemia 0.9
elevated ALT 0.9
decreased neutrocyte 0.9
supraventricular extrasystole 0.9
hypotension 0.9
TAS3681 AR and AR-SV antagonist phase 1 NCT02566772a 56 mCRPC post ARPI and post chemo 0 DLT and safety 3 DLT (prolonged QTc and hypertension) at 600 mg QD and 400 mg BID not reported 21.4 NCI CTCAE (v4.0) not reported
AR PROTAC degrader BMS-986365

(CC-94676)		 dual effect (AR degrader and AR antagonist) phase 1 39293515 part A (dose escalation): 27 mCRPC post ARPI and post chemo 0 safety; define MTD and/or RP2D MTD not reached. 1 DLT (prolonged QTc): 900 mg BID prolonged QTc 14 NCI CTCAE (v5.0) antiarrhythmic drugs that prolong the QT were an exclusion criteria
part B (dose expansion): 68 NA prolonged QTc 9
bradycardia 3
syncope 1
hypertension 1
dyspnea and general oedema 1
Bavdegalutamide = ARV110 phase 1 NCT03888612b 18 mCRPC post ARPI +/- post chemo 0 MTD and RP2D 1 DLT (elevated ALT/AST and acute renal failure) at 280 QD twice daily AST/ALT elevation 11 NCI CTCAE (v5.0) Rosuvastatin
phase 1/2 NCT03888612c 153 mCRPC post ARPI +/- post chemo 0 efficacy (ORR) NA anemia 5 NCI CTCAE (v5.0) not reported
diarrhea 2
fatigue 1
vomiting 1
nausea 1
AST elevation 1
ARV-766 phase 1/2 NCT05067140d 103 mCRPC post ARPI +/- post chemo 0 safety (phase 1); clinical activity (phase 2) No DLT observed; MTD not reached fatigue 3 NCI CTCAE (v5.0) not reported
nausea 1
diarrhea 1
HP518 phase 1 NCT05252364e 22 mCRPC post ARPI and ≤ 1 line of chemo 0 safety and RP2D No DLT observed not reported NCI CTCAE (v5.0) not reported
AR-V inhibitor Niclosamide AR-V inhibitor, and Pi3K/AKT/mTOR, NF-κB, and Wnt-signaling inhibitor phase 1 29856824 5 mCRPC post ARPI Enzalutamide safety MTD = 500 mg TID. 2 DLT (nausea, vomiting, diarrhea and colitis) at 1000 mg TID nausea 20 NCI CTCAE (v4.0) not reported
vomiting 20
diarrhea 40
colitis 20
abdominal pain 20
Niclosamide reformulated (PDMX1001) phase 1b 33737681 9 mCRPC abiraterone naive (post enzalutamide and/or chemo authorized) Abiraterone MTD and RP2D No DLT observed fatigue 11 NCI CTCAE (v4.0) not reported
abdominal pain 11
hypoalbuminemia 11
anemia 11
hyperglycemia 11
AR-NTD inhibitor (anitens) EPI-506 phase 1 34843005 28 mCRPC post ARPI +/- post chemo 0 safety MTD not reached. 6 DLT observed in 4 patients (at 640 mg; 1800 mg BID; 3600 mg QD and 3600 mg QD) elevated amylase 4 NCI CTCAE (v4.03) not reported
abdominal pain 4
elevated ALT 4
elevated AST 4
nausea 4
vomiting 4
Masofaniten (EPI-7386) phase 1 NCT05075577f 18 mCRPC ARPI naive (post chemo authorized) Enzalutamide safety Not reported rash 6 NCI CTCAE (v5.0) not reported
hypertension 6
back pain 6
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Links for abstracts or oral presentations.

FIGURE 1.

FIGURE 1

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Anti tumoral activity of different class of drugs inhibiting the androgen receptor pathway with main mechanisms of resistance related to androgen receptor pathway.

Androgen biosynthesis inhibitors

ODM-208 is an oral selective inhibitor of CYP11A1, an enzyme that catalyzes the transformation of cholesterol in pregnenolone, which is the first step of production of all androgenic and nonandrogenic steroid hormones. In the phase I CYPIDES study [9▪▪], despite prophylactic replacement therapy, the main adverse event was adrenal insufficiency, which was observed in 17 patients (36%), including 16 cases of SAE (34%). Eight cases (17.0%) led to treatment interruption, including one case (2.1%) of treatment withdrawal [9▪▪]. Daily (q.d.) dose appeared to be associated with adrenal insufficiency incidence (29.4% all grades included when q.d. dose was less than 25 mg, increasing to 40.0% with greater doses) and severity. In the phase 2 CYPIDES study [9▪▪], the incidence of adrenal insufficiency dropped to six patients (13.3%), of which half were mild or moderate cases and the remaining half were considered as SAE that led to treatment discontinuation (6.7%). Other main grade ≥ 3 AEs across the phase 1 and phase 2 trials included anemia (14.9 and 10.9%, respectively), hypertension (10.6 and 6.7%, respectively) and pulmonary embolism (10.6 and 6.7%, respectively).

Galeterone is a CYP 17 inhibitor, AR antagonist and AR degrader. The main grade ≥ 3 AEs in a phase 1 trial was alanine aminotransferase (ALT) (16.3%) and aspartate aminotransferase (AST) (6.1%) elevation, and the same patterns were found in the phase 2 trial (10.7 and 3.6%, respectively) [10]. After disappointing results in phase 3 (the study was terminated early), the development of galeterone is currently stopped [11].

Novel androgen receptor antagonists

HC-1119 is a deuterated form of enzalutamide that has a slower metabolism and greater drug exposure compared to “regular” enzalutamide, which could lead to a lower dose and ultimately a better safety profile, notably regarding brain exposure and side effects. The phase 1 study included 24 (part A – dose escalation) and 19 (part B – dose expansion) patients, with five cases of grade ≥ 3 adverse event overall, including hypertension (two cases), anemia, neutropenia and proteinuria (one case each) [12]. No grade ≥ 3 fatigue or seizures have been observed.

SHR3680 is another AR antagonist that presents similar antitumor effects to enzalutamide (preclinical data) but with lower distribution in the brain, potentially reducing neurological side effects. In the phase 1/2 study that recruited 197 patients, 23 cases (11.7%) of treatment-related adverse events (TRAE) of grade ≥ 3 occurred, mainly involving cytopenia (three cases of leukopenia, one of anemia) [13]. No seizures were reported, nor grade 3 or 4 fatigue.

GT0918 (proxalutamide) is a novel AR antagonist that binds the AR LBD with a higher affinity than enzalutamide, including both wild-type and mutant AR. In the phase 1 study, no dose limiting toxicity (DLT) or grade ≥ 3 adverse events were observed [14]. In the phase 2 trial, 14 grade ≥ 3 AEs were reported among 108 patients (13%), mainly involving metabolic and nutritional aspects (weight loss, decreased appetite, hypertriglyceridemia, hypokalemia and hypophosphatemia; n = 6); heart and vascular diseases (two cases of hypertension, one of hypotension, and one of supraventricular extra systole) and hematological toxicity (three cases of anemia, one of neutropenia) [15].

Finally, TAS3681 is another AR and AR-V antagonist, that demonstrated antitumor efficacy in AR-SV-positive enzalutamide-resistant castration-resistant prostate cancer (CRPC) models. To date, only a conference abstract about a phase 1 dose escalation study including 56 heavily pretreated patients is available, in which three DLTs (two prolonged corrected QT interval (QTc) and one grade 3 hypertension) and 12 (21.4%) grade ≥ 3 TRAE (not detailed) were observed [16]. The most common TRAEs of any grade were mainly digestive: nausea (57%), hyperbilirubinemia (37.5%), vomiting (30.4%), and nausea (28.6%).

Androgen receptor PROTAC degraders

Proteolysis-targeting chimera (PROTAC) are heterobifunctional molecules that bind to a protein of interest on one side and to an E3 ligase on the other, inducing ubiquitination of the protein of interest and its degradation through the proteasome. In prostate cancer, many PROTAC molecules targeting AR are currently under development. Among them, BMS-986365 (CC-94676) is an AR degrader with a dual effect, as it is also an AR antagonist. In a phase 1 study, conducted with 27 (part A – dose escalation) and 68 (part B – dose expansion) patients, the main grade ≥ 3 TRAE were prolonged QTc, with two cases (14%) in part A and six (9%) cases in part B (17). All of them occurred within the first two cycles of treatment and resolved to grade ≤ 2 after dose reductions. Other grade ≥ 3 TRAEs or SAEs included bradycardia (3%), syncope, hypertension, dyspnea and generalized edema (1% each).

Another AR PROTAC degrader is Bavdegalutamide (ARV-110). In a phase 1 study (18 patients), two (11%) grade ≥ 3 AST/ALT elevations occurred (including one DLT, associated with acute renal failure), both of them concomitant to rosuvastatin medication, which has since been prohibited [18]. No other grade 3 or 4 adverse events were reported. To date, in a phase 1/2 study with 153 patients, main grade ≥ 3 TRAE were anemia (5%) and digestive disorders including diarrhea (2%), nausea (1%), vomiting (1%) and AST elevation (1%) [19].

Other AR-targeting PROTAC degraders under development have been only presented in recent (2024) conferences. ARV-766 showed limited grade ≥ 3 toxicity in an abstract presenting the initial results of a phase 1/2 study that included 103 patients: fatigue (3%), diarrhea (1%) and nausea (1%) [20]. Finally, a phase 1 study is ongoing for HP-518. Preliminary results reported no DLT after enrollment of 22 patients [21].

Others

Niclosamide is an antihelminthic drug that preclinically showed an antitumor effect in CRPC, inducing degradation of constitutively active AR-V and inhibiting other drug resistance pathways such as Pi3K/AKT/mTOR or Wnt-signaling. Because it does not degrade the full-length AR, its development has been studied in combination with ARPIs (i.e. abiraterone or enzalutamide). However, the phase 1 study was rapidly closed after enrolment of five patients because plasma concentrations at the maximum tolerated dose (MTD; 500 mg TID) were below the therapeutic threshold [22]. To improve absorption and oral availability, a reformulated form of niclosamide was developed and evaluated in a phase 1b study in association with abiraterone [23]. Therapeutic concentrations based on preclinical studies were reached and among nine patients included, five grade 3 toxicities were found: abdominal pain, fatigue, anemia, hypoalbuminemia and hyperglycemia. No DLTs were reported.

EPI-506 is the first of a new class of drugs (“anitens”) that inhibit the AR N-terminal domain (AR-NTD), blocking its binding to DNA and thus its transcriptional activity, and potentially overcoming resistance mechanisms such as AR-LBD mutations or AR-V. The phase 1 trial closed after enrolment of 28 patients without reaching the maximum tolerated dose (MTD), due to poor oral availability [24]. Principal tolerance signals were about gastrointestinal adverse event, with six DLT occurring in four patients (abdominal pain, elevation of ALT, AST and amylase, nausea and vomiting). Of note, 18 pills a day were required at the highest dose, creating concerns about the possible imputability of excipients for some of these side effects.

Masofaniten (EPI-7386) is a next-generation “aniten” currently evaluated in association with enzalutamide. Data from the phase 1 trial were presented during the 2024 ESMO conference, with a similar safety profile to enzalutamide monotherapy. Among 18 patients, three grade 3 toxicities were declared (rash, hypertension and back pain) [25]. The phase 2 trial is ongoing.

DISCUSSION

This narrative review describes the toxicities reported with new generation of hormone therapies, beyond ARPIs usually prescribed in advanced PCa (e.g. “-amides” and abiraterone). Emergent AEs were reported especially adrenal insufficiency-like events using CYP11A1 inhibitors and cardiac disorders. Different profiles of toxicities were also related to either a combination with usual ARPIs or a development of new compounds with multiple effects on the AR pathway (mainly AR antagonism).

Despite glucocorticoid and mineralocorticoid replacements requested with CYP11A1 inhibitors, the phase II trial reported roughly 6% ≥ grade 3 toxicity related to adrenal insufficiency [9▪▪]. While mineralocorticoid replacement was not changed, different protocols of glucocorticoids replacement were tested and dexamethasone 1–1.5 mg q.d. was considered as the most appropriate compared to hydrocortisone 40–80 mg q.d. and prednisone 5–20 mg q.d. Although effective, the toxicity of this drug has to be handled by well trained physicians not only for potential dose adjustments, but also to provide patient education regarding adrenal insufficiency, including emergency kits and increasing doses of glucocorticoids replacement in case of acute events such as infection or surgery. With the development of different phase 3 trials investigating opevesostat (i.e. ODM-208) in earlier lines (NCT06136624, NCT06136650), one concern remains regarding the toxicity of such a replacement (i.e. dexamethasone 1.5 mg QD and fludrocortisone 0.1 mg QD) with a long-term exposure, for example skin toxicity, bone loss, hypertension as well as diabetes. In addition, opportunistic infections such as Pneumocystis jirovecii have to be avoided using antibiotic prophylaxis. Development of Galeterone (CYP 17 inhibitor, AR antagonist and degrader) was stopped by a negative phase 3 trial. With only 38 patients included, this trial was terminated early due to a majority of patients censored (for progressive disease) before the first radiographic assessment. This highlights the poor prognosis associated with ARV7+ mCRPC. Liver toxicity was the main TRAE and was consistent across different trials. Regarding AR degraders, prolonged QTc might be related to degraders with AR antagonism [17▪], since it was not reported with other degraders. While being the main TRAE of BMS-986365, prolonged QTc occurred early, remained asymptomatic and resolved with decreasing dose. Recent meta-analysis suggests that ARPIs combined with ADT increase cardio vascular disorders in patients with advanced prostate cancer versus ADT alone [26]. Among these ARPIs, enzalutamide was statistically associated with prolonged QTc and torsade de pointe. In vitro, this drug inhibits repolarizing potassium-currents in models of cardiomyocytes and then delays ventricular repolarization [27]. Of note, two events of sinus bradycardia were also reported for DLTs. Using in-vivo models, enzalutamide without ADT was also shown to induce significant bradycardia without mechanistic demonstration [28]. A phase 3 trial is ongoing for chemo-naive patients with mCRPC (rechARge NCT06764485). New AR antagonists seem to be well tolerated except TAS3681 [16], with more than 20% grade 3 and 3 DLTs reported, including prolonged QTc. Some new AR antagonists such as SHR3680 [13] were developed with lower blood brain barrier penetrance than enzalutamide. If asthenia was not reported among ≥ grade 3 adverse events, a past history of seizure was an exclusion criterion limiting their potential advantage. Other pathways to decrease central nervous system AEs are being investigated, such as this randomized phase 2 trial using a lower dose of enzalutamide (120 vs. 160 mg/day) in frail patients with mCRPC [29]. Patients with lower doses experienced less fatigue without lower blood exposure to the drug, suggesting it is possible to decrease the dose in frail patients, while maintaining efficacy. Recent AR-V inhibitors were developed in combination with either enzalutamide or abiraterone. A lower toxicity and no DLT were reported using the new compound (e.g. niclosamide reformulated PDMX 1001) with abiraterone. While NTD inhibitors seem to be well tolerated, some data are missing regarding DLT/MTD (NCT05075577) and oral bioavailability might be an issue for the development of this compound [24].

With only 11 out of the 17 studies reported here published, mainly phase I/II trials, some elements are missing in the available data. Adverse events were not always noted as treatment-emergent adverse events (TEAEs) as opposed to treatment-related adverse events (TRAEs), and the trials are too recent to report long-term toxicity. With the exception of one study on ARV110 and statins showing an increase rate of cytolysis [18], there was no other available data regarding potential drug-drug interactions (DDIs) with these new compounds, especially when they were tested with another ARPI, which are all well known for DDI, with potential effects on different isoforms of Cytochrome P450 (mainly CYP2D6 and CYP3A4) [30]. In these earlier trials, quality of life is not investigated yet, however, patient-reported outcomes are still important for further developments, in this chronic disease setting with potential long-term exposure to these treatments. Finally, with the advances of precision medicine, the efficacy/toxicity ratio will become more acceptable, as illustrated by a maintained efficacy of ODM-208 or BMS-986365 in patients with mutated AR LBD Pca.

CONCLUSION

In this narrative review, adrenal insufficiency-like events and cardiac disorders were the main specific adverse events associated with new hormonal therapies used to treat advanced PCa. While these treatments are still under development, they will have to be handled by well trained physicians in order to better manage acute and long-term toxicities.

Acknowledgements

The authors thank Pippa McKelvie Sebileau for medical editing in English.

Financial support and sponsorship

None.

Conflicts of interest

G.R. and D.T. were investigators in the phase I/II CYPIDES trial. All the other authors do not have any conflict of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest

  • ▪▪ of outstanding interest

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