Relugolix in Combination with Androgen Receptor Pathway Inhibitors in the Treatment of Metastatic Prostate Cancer: A Clinical Perspective

Abstract

Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, has been established as an effective androgen deprivation therapy (ADT) for advanced prostate cancer, offering advantages over traditional GnRH agonists. The combination of relugolix with androgen receptor pathway inhibitors (ARPIs) is increasingly utilized in clinical practice, necessitating an understanding of its pharmacokinetics, efficacy, safety, and drug–drug interactions. This review explores the real-world data and clinical studies evaluating relugolix coadministration with ARPIs, including enzalutamide, abiraterone, apalutamide, and darolutamide. Pharmacokinetic interactions, particularly via the CYP3A4 enzyme system and P-glycoprotein (P-gp) transporter, influence drug exposure and, in theory, necessitate dose adjustments in certain combinations. However, clinical studies and real-world studies suggest that relugolix maintains testosterone suppression when combined with ARPIs even if administered in a standard dose. While these findings support the efficacy and safety of relugolix-based combination therapy, further large-scale prospective trials are needed to refine treatment recommendations and provide information on long-term outcomes.

Key Points

Relugolix is an oral medication used to lower testosterone levels in men with advanced prostate cancer. It works differently from traditional hormone treatments by avoiding sudden testosterone spikes that can worsen the disease. It possibly also has a lower risk of heart-related side effects compared with leuprolide, a commonly used alternative.

Treating advanced prostate cancer often requires combining testosterone-lowering therapy with other medications that block cancer growth, such as enzalutamide, apalutamide, abiraterone, and darolutamide. However, concerns about how these drugs might interact have limited the wider use of relugolix.

Recent clinical studies and real-world experiences suggest that relugolix can be safely used with these additional treatments without reducing its effectiveness. These findings are promising, although more research is needed to confirm the best way to use relugolix as part of combination therapy.

Introduction

Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, has demonstrated efficacy and safety as an androgen deprivation therapy (ADT) for advanced prostate cancer.

In the pivotal phase III HERO trial, relugolix achieved a sustained castration rate of 96.7% over 48 weeks, demonstrating non-inferiority and potential superiority to intramuscular leuprolide depot. The rapid testosterone suppression by relugolix, without the initial testosterone surge and tumor flare associated with GnRH agonists provides a distinct advantage over GnRH receptor agonists [1, 2].

Furthermore, relugolix exhibited a 54% reduction in major adverse cardiac events compared with leuprolide [1]. Although cardiac safety was not an endpoint of the HERO study, and there are ongoing studies specifically addressing the issue, the favorable cardiovascular safety profile of relugolix compared with GnRH analogs has led many physicians to prefer it as an ADT of choice for patients with preexisting cardiovascular conditions. The oral administration route offers convenience and avoids injection-site reactions, although adherence monitoring remains essential [3]. Real-world data suggest that relugolix is frequently used in combination with other prostate cancer medications, indicating its integration into standard treatment regimens [4, 5].

The recommended dosing regimen of relugolix involves a 360 mg loading dose followed by a 120 mg daily dose, which has been shown to achieve rapid and sustained testosterone suppression, reaching castration levels (< 50 ng/dL) by day 2 and profound castration levels (< 20 ng/dL) by day 9 [1]. Relugolix exhibits a high predictiveness in its pharmacokinetic/pharmacodynamic models, that are consistent with actual clinical data and support its dosing recommendations, even in cases of temporary treatment interruption [6].

Current treatment algorithms require early use of androgen receptor pathway inhibitors (ARPIs) in patients with metastatic prostate cancer (mPC). It is an important question whether oral ADT using relugolix can replace conventional parenteral ADT.

Methods

For this narrative review, publications and abstracts of retrospective and prospective studies were searched in Medline and Google Scholar using the terms “relugolix,” “relugolix metabolism,” and the terms “relugolix combination” and “relugolix interaction” each with “apalutamide,” “abiraterone,” “enzalutamide,” “darolutamide,” “niraparib,” “olaparib,” “talazoparib,” and “rucaparib.” References from the identified articles were reviewed to identify further sources. Ongoing clinical trials with relugolix in combination with other systemic therapies for mPC were identified using the ClinicalTrials.gov webpage.

ARPIs and Their Potential Interactions with Relugolix

Relugolix is mainly metabolized by the CYP3A subfamily of cytochrome P450 enzymes, which are responsible for the majority of drug metabolism in the liver. This indicates that drugs or substances that induce or inhibit CYP3A could significantly affect plasma levels and the efficacy of relugolix [7] (Tables 1 and 2). CYP2C8 plays a lesser role in the metabolism of relugolix, suggesting that interactions involving this enzyme are less likely to impact the pharmacokinetics significantly [7].

Table 1.

Understanding CYP3A4 inducers and substrates: relugolix and apalutamide as examples

CYP3A4 is a key enzyme in the cytochrome P450 family that metabolizes many drugs in the liver and intestinal wall. Drugs can interact with CYP3A4 in different ways:

Substrate: A drug that is metabolized by CYP3A4. The enzyme breaks down the drug, affecting its concentration and activity in the body

Inducer: A drug that increases the activity of CYP3A4, leading to faster metabolism of substrates. This can reduce the levels of the substrate drug, potentially diminishing its therapeutic effect

Relugolix and apalutamide interaction

1. Relugolix as a substrate

Relugolix is metabolized by CYP3A4, making it a substrate. When CYP3A4 activity increases, relugolix is metabolized more quickly, reducing its plasma concentration and potentially its efficacy in suppressing testosterone levels

2. Apalutamide as an inducer

Apalutamide is a strong inducer of CYP3A4. It increases the enzyme’s activity, accelerating the metabolism of drugs that are CYP3A4 substrates. When relugolix is taken together with apalutamide, its plasma levels decrease due to enhanced metabolism

3. Clinical implication of the interaction

In theory, to counteract the enhanced metabolism caused by CYP3A4 inducers, the dose of relugolix may need to be adjusted to ensure that enough relugolix remains in circulation to achieve its desired therapeutic effect—maintaining testosterone at castration levels. However, this need for increased dosing has not been corroborated by clinical studies. Close monitoring of testosterone levels is important, particularly in advanced prostate cancer, where testosterone suppression is critical

Table 2.

A summary of metabolism and potential interactions between ARPIs and relugolix

ARPI	CYP3A4 substrate	CYP3A4 inducer	CYP3A4 inhibitor	Possible interaction with relugolix
Apalutamide	Yes	Strong	No	Reduces relugolix exposure by inducing CYP3A4, although clinical studies do not show reduced effect of relugolix on testosterone suppression
Enzalutamide	Yes	Moderate	No	May reduce relugolix exposure, but clinical studies suggest a neutral net effect due to compensatory mechanisms
Darolutamide	Yes	Weak	No	Minimal impact on relugolix; no dose adjustment needed
Abiraterone	Yes	No	Yes	May increase relugolix exposure, but no clinical significance noted in studies

Relugolix is a substrate of P-glycoprotein (P-gp), an efflux transporter found in the intestines, liver, kidneys, and blood–brain barrier [8]. P-gp plays a crucial role in limiting drug absorption and enhancing drug elimination by actively transporting substrates out of cells [9]. In the intestine, P-gp can pump relugolix back into the intestinal lumen, reducing its absorption. In the liver and kidneys, P-gp contributes to relugolix elimination by increasing its excretion.

In contrast to leuprolide, which is not a P-gp substrate, the absorption and elimination of relugolix can be influenced by P-gp inhibitors or inducers, including some ARPIs. P-gp inhibitors such as abiraterone may increase relugolix plasma concentrations, potentially leading to enhanced efficacy but also a higher risk of side effects. P-gp inducers (e.g., apalutamide and enzalutamide) may decrease relugolix plasma concentrations, potentially reducing its effectiveness (Table 3).

Table 3.

A summary P-glycoprotein (P-gp) interactions of ARPIs and their implications for relugolix

ARPI	P-gp interaction	Implications for relugolix
Abiraterone	Inhibits P-gp	May increase relugolix exposure, potentially enhancing its effects and side effects.
Apalutamide	Induces P-gp	May reduce relugolix levels.
Darolutamide	Substrate and weak inhibitor of P-gp	Minimal effect on relugolix expected.
Enzalutamide	Induces P-gp	May lower relugolix plasma concentration.

The co-administration of androgen receptor pathway inhibitors (ARPIs) with relugolix presents a potential drug–drug interaction (DDI) due to the CYP3A4-inducing properties of certain ARPIs. The extent of this interaction varies depending on the specific ARPI used (Tables 2 and 3). Regardless of the ARPI used, regular testosterone monitoring is recommended to ensure adequate androgen suppression.

Apalutamide

Apalutamide is predominantly metabolized by cytochrome P450 enzymes, specifically CYP2C8 and CYP3A4. The contribution of these enzymes changes with repeated dosing due to autoinduction, with CYP2C8 contributing 58% and CYP3A4 13% after a single dose, and 40% and 37% at steady state, respectively [10, 11]. The primary active metabolite of apalutamide is N-desmethyl-apalutamide, which is formed through demethylation. This metabolite is pharmacologically active and contributes significantly to the drug’s therapeutic effects [11, 12]. In addition, an inactive carboxylic acid metabolite (M4) is also formed [11]. The metabolism of apalutamide can be affected by CYP2C8 and CYP3A4 inhibitors and inducers. For instance, co-administration with gemfibrozil (a CYP2C8 inhibitor) increases apalutamide exposure by 68%, while rifampicin (a CYP3A4 inducer) decreases it [10, 13].

Apalutamide can also affect the metabolism of other drugs. It significantly reduces the systemic exposure of drugs metabolized by CYP3A4, CYP2C9, and CYP2C19, such as midazolam and omeprazole, indicating its potential as a perpetrator in drug-drug interactions [13]. Moreover, apalutamide can reduce the systemic exposure of other drugs metabolized by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) [14].

The potential interaction between relugolix and apalutamide is an important consideration in the treatment of prostate cancer (Table 1). Apalutamide is metabolized primarily by CYP2C8 and CYP3A4 enzymes, potentially affecting the metabolism of other drugs metabolized by these pathways [10, 13]. In addition, apalutamide may decrease relugolix levels owing to P-gp induction [15]. Thus, apalutamide is a strong inducer of CYP3A and a P-gp inducer. According to the Federal Drug Agency (FDA) prescribing information, the dose of relugolix should be doubled when apalutamide is coadministered, and this has been adhered to in a study by De la Cerda et al. [16, 17]. A recent pharmacokinetics analysis by these authors indicates that the levels of relugolix given at a double maintenance dose of 240 mg with apalutamide are similar to levels of relugolix when administered in monotherapy (see below) [18].

However, a prospective study by Brown et al. has shown that the combination of relugolix and apalutamide maintains effective testosterone suppression without requiring dose adjustments, indicating minimal pharmacokinetic interaction [19].

The question of relugolix dose when coadministered with apalutamide is currently open, as the maintenance of the castration status may not necessarily require the doubling of the relugolix dose.

Relugolix, conversely, does not have significant interactions with CYP enzymes, which suggests that it does not alter the pharmacokinetics of apalutamide significantly [19].

Enzalutamide

Enzalutamide undergoes extensive hepatic metabolism primarily mediated by cytochrome P450 enzymes, particularly CYP3A4 and CYP2C8 [20–22]. Enzalutamide is primarily metabolized by CYP3A4 into N-desmethyl enzalutamide, which retains pharmacological activity and contributes to the drug’s overall effect [23, 24]. The drug also induces CYP3A4, which can lead to altered metabolism of other drugs that are substrates of this enzyme [25, 26]. The induction of CYP3A4 by enzalutamide can significantly reduce the plasma concentrations of co-administered drugs metabolized by this enzyme, such as cabazitaxel and oxycodone, potentially leading to subtherapeutic levels [24–26]. Enzalutamide and N-desmethyl enzalutamide also affect P-glycoprotein (P-gp) substrates [27, 28]. The combination of CYP3A4 induction and P-gp interaction can decrease the exposure of drugs such as apixaban and rivaroxaban, and potentially, relugolix (7, 8). However, a study indicated that enzalutamide did not alter the trough concentrations of relugolix, suggesting a neutral net effect on relugolix exposure, and testosterone suppression by relugolix was not affected [29].

Abiraterone

Abiraterone is a potent inhibitor of the CYP17A1 enzyme crucial in androgen biosynthesis and has a complex metabolism. Abiraterone acetate, the prodrug, is rapidly converted to abiraterone, which is further metabolized to Δ4-abiraterone (D4A). D4A is a potent inhibitor of CYP17A1 and other steroidogenic enzymes, and it also antagonizes the androgen receptor (AR) [30, 31]. D4A undergoes 5α-reduction to form 3-keto-5α-abiraterone, an AR agonist that can promote prostate cancer progression. This metabolite is present at higher concentrations than D4A in patients and is associated with tumor-promoting activity, and its formation can be prevented by dutasteride, a 5α-reductase inhibitor [30]. The 5β-reduction pathway results in inactive metabolites [30]. Abiraterone and its metabolites undergo glucuronidation, primarily by UGT1A4, forming glucuronide derivatives that are detectable in patients. This pathway is significant for drug clearance and can be influenced by genetic variations in UGT1A4 [32]. In addition, the gut microbiota can metabolize abiraterone, contributing to its biotransformation [33].

Abiraterone can inhibit CYP3A4 and CYP2C8, affecting the metabolism of other drugs, and potentially increasing relugolix concentrations [34, 35]. In addition, abiraterone may increase relugolix levels due to P-gp inhibition [36]. However, in the clinical setting, no new safety signals were observed when relugolix was used in combination with abiraterone [5, 17].

Prednisone, always used in conjunction with abiraterone, is also metabolized by CYP3A4. There are no data in the literature on potential interaction with relugolix, but given the results from relugolix–abiraterone coadministration studies, the effect is probably not clinically relevant.

Darolutamide

Darolutamide is a nonsteroidal androgen receptor antagonist with relatively low interaction potential and a favorable cardiovascular toxicity profile [37]. It appears to be a partner of choice for relugolix in the treatment of patients with cardiovascular comorbidities [38].

Darolutamide is primarily metabolized in the liver by CYP3A4 and aldehyde oxidase (AO) into its active metabolite, keto-darolutamide. Both the parent drug and the metabolite contribute to its pharmacological activity. Darolutamide has a lower potential for drug–drug interactions than enzalutamide owing to its lower impact on CYP enzymes, but it still induces CYP3A4 and inhibits P-glycoprotein (P-gp) and BCRP transporters, which could affect the pharmacokinetics of co-administered drugs [39–41]. Since both darolutamide and relugolix are metabolized by CYP3A4, there is a theoretical concern that darolutamide, as a CYP3A4 inducer, might reduce the plasma levels of relugolix by increasing its metabolism. This could potentially lead to a decrease in relugolix efficacy, potentially affecting testosterone suppression.

Coadministration of Relugolix and ARPIs—Clinical Data

The findings of several small prospective clinical studies and evidence from real-world cohorts support the use of relugolix as a safe and effective component of combination therapy for advanced prostate cancer while stressing the need for additional safety data regarding its use with other therapies. These interim results provide a foundation for continued exploration of relugolix in combination treatments and provide reassurance to patients and physicians willing to use the combinations.

Brown et al. (2023)

The results of a phase II sub-study demonstrate that the coadministration of relugolix and apalutamide effectively maintained castrate testosterone levels (< 50 ng/dL) in patients with high-risk localized prostate cancer following radical prostatectomy. All 12 participants achieved castrate testosterone levels after 2 weeks of relugolix monotherapy (standard dosing of 360 mg loading dose on day 1, followed by 120 mg daily dose from day 2), and 11 evaluable patients maintained these levels through day 28 of combination therapy without the need for relugolix dose adjustments. However, although testosterone recovery is known to be rapid after relugolix cessation [42], a follow-up period exceeding 28 days would have been more appropriate in this context, given that the suppressive effects of relugolix are not completely nullified by concomitant apalutamide, but only possibly mitigated to some extent.

The safety profile was consistent with previously reported data for each drug, with hot flushes being the most common treatment-emergent adverse event and no grade ≥ 3 adverse events or treatment discontinuations. These findings suggest that the combination of relugolix and apalutamide at standard doses offers a safe and effective strategy for testosterone suppression despite the theoretical critical interaction between the agents. However, the cohort was small and larger studies are necessary to confirm these observations and to evaluate long-term outcomes of this treatment approach [19].

De La Cerda et al. (2023)

In this phase I clinical trial, the safety and tolerability of relugolix were evaluated in combination with abiraterone or apalutamide for the treatment of advanced prostate cancer. First results were published in 2023, with a recent update published in 2025 [17, 18]. The study enrolled 24 patients each for relugolix–abiraterone and relugolix–apalutamide cohorts, and 21 and 20 patients were evaluable, respectively. Of note, the dose of relugolix was doubled from 120 mg to 240 mg daily in the relugolix–apalutamide cohort, in accordance with FDA prescribing information [16]. The mean exposure to relugolix was 48 weeks. Adverse events were mostly mild-to-moderate in severity and consistent with the known safety profiles of the individual drugs, with no significant trends observed in clinical laboratory results, vital signs, or electrocardiographic parameters. Testosterone levels remained below castration thresholds throughout the 12-week treatment period, including during the transition from prior ADT to relugolix [17]. Of note, 78% of patients in the relugolix–abiraterone arm and 54% of patients in the relugolix–apalutamide arm received GnRH analogs as their previous therapy. Since testosterone recovery is frequently delayed beyond 90 days after treatment cessation in patients treated with leuprolide [43], the previous GnRH treatment may have contributed to castration status in these individuals.

Importantly, pharmacokinetics has been reported in the recent update of this study [18]. Relugolix plasma levels remained consistent across weeks 2, 4, 8, and 12, indicating that steady-state conditions had been reached. In the relugolix–apalutamide cohort, the concentrations of relugolix at the 240 mg daily dose were comparable to those reported in prior studies involving relugolix monotherapy at 120 mg daily. Plasma concentrations of apalutamide and N-desmethyl apalutamide remained stable over the 12-week treatment period.

McKay et al. (2023)

In the REAL-ADT COMBO Study, a real-world analysis of US electronic medical records from 89 urology practices, the utilization of ADT with leuprolide or relugolix and their combination with other PC medications was evaluated. Among 51,735 patients treated with ADT in 2021, 88.1% received leuprolide and 6.0% received relugolix. Combination therapy with other PC medications was more frequent among relugolix users than leuprolide users (22.5% versus 19.5%, p < 0.0001). In patients newly initiating ADT, combination therapy was also higher for relugolix users (15.8%) compared with leuprolide users (10.9%). ARPIs were the most frequently observed co-therapies in both groups, with enzalutamide being common to both. Among patients receiving relugolix, 9.0% were treated with enzalutamide, 6.9% with apalutamide, 5.9% with abiraterone, and 1.1% with darolutamide. The published data do not specify the dose of relugolix in patients also receiving apalutamide. These findings suggest that relugolix is relatively frequently used in combination with other PC medications in clinical practice [4].

George et al. (2023)

A subgroup and pharmacokinetic/pharmacodynamic analysis of the phase III HERO trial evaluated the impact of concomitant prostate cancer therapies on the efficacy and safety of relugolix compared with leuprolide in men with advanced prostate cancer. Among the 934 patients randomized to receive either relugolix 120 mg once daily or leuprolide injections every 12 weeks, 13.4% received additional therapies affecting testosterone levels, with enzalutamide (2.7%) and docetaxel (1.3%) being the most frequently used. Sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks was comparable between patients receiving relugolix alone and those receiving concomitant enzalutamide or docetaxel. Safety profiles were similar, with serious adverse events more frequently observed in patients receiving combination therapy, reflecting underlying disease severity and the safety profiles of the additional agents. Pharmacokinetic analyses demonstrated no clinically significant impact of enzalutamide on relugolix exposure, suggesting a neutral net effect of the induction and inhibition properties of enzalutamide on relugolix metabolism. These findings support the combination of relugolix with enzalutamide without the need for dose adjustments [29].

Guan et al. (2024)

A retrospective analysis of medical records from Houston Methodist Genitourinary Oncology identified 152 hormone-naive patients with prostate cancer treated with relugolix plus ARPIs between September 2021 and July 2023. The cohort had a median age of 71 years (range 48–96), with 90% exhibiting at least one cardiovascular risk factor, such as hypertension (72%), hyperlipidaemia (52%), obesity (41%), and diabetes (26%). The ARPIs included darolutamide (78%), abiraterone (14%), apalutamide (7%), and enzalutamide (1%). Median treatment exposure was 8 months (range 1–21), and the patient compliance was very high. All patients achieved castrate testosterone levels, with 90% reaching levels below 20 ng/dL. Prostate-specific antigen (PSA) response was robust, with 55% of patients achieving PSA < 0.1 ng/mL within a median of 4 months. PSA declines of ≥ 50% and > 90% were observed in 91% and 75% of patients, respectively. Treatment discontinuation due to adverse events occurred in 7% of patients. Major adverse cardiac events were observed in 2% of cases (one sudden death, one case of heart failure, and one myocardial infarction). Grade 3 fatigue and liver function test elevations were each reported in 1% of patients. No clinically significant drug–drug interactions were identified [38].

Kasparian et al. (2023)

The study by Kasparian et al. was a real-world study of relugolix both as monotherapy and in combination with ARPIs. Among the 91 patients prescribed relugolix, 24 (34%) received it in combination with other prostate cancer therapies. The androgen receptor-targeted agents used included enzalutamide (ten patients; 43% of combination therapy users), abiraterone (eight patients; 35%), bicalutamide (four patients; 17%), and apalutamide (three patients; 13%). The median follow-up time of 5 months (range 1–12 months) was relatively short. All patients tested for testosterone levels (61 patients) achieved stable castration levels, even those who missed relugolix doses. However, the article does not specify how many of these patients received relugolix in monotherapy and how many in combination. Many enrolled patients switched from other types of ADT, including 19% switching from leuprolide, and possible long-term testosterone suppression by the previous medication may have occurred. The study found no new or unexpected safety concerns when relugolix was used in combination therapy. However, the toxicity profile varied, with certain adverse events more frequently reported among patients on combination therapy compared with those on relugolix monotherapy. Fatigue was significantly more common in combination therapy compared with monotherapy (39% versus 19%), while pain was also reported more frequently in the combination group (30% versus 6%), although this may reflect more advanced disease in patients receiving combination treatment. Weight gain was observed in 22% of patients on combination therapy, compared with 13% in monotherapy. Interestingly, behavioral changes, such as mood swings or cognitive effects, were paradoxically lower in the combination group (4%) than in monotherapy (23%). The incidence of hot flashes was similar between groups, occurring in 38% of combination therapy patients versus 40% in monotherapy. However, urinary symptoms were notably less frequent in the combination group (4%) compared with monotherapy (26%). Regarding cardiovascular toxicity, the study identified five major adverse cardiac events (MACE) among the relugolix-treated population. While the total incidence of cardiovascular events was low, patients receiving enzalutamide in combination showed a slightly higher tendency for cardiovascular complications, although statistical significance was not reached owing to a small sample size and low numbers of events [5].

Potential Interaction between PARP Inhibitors and Relugolix

Poly-ADP-ribose polymerase (PARP) inhibitors including olaparib, rucaparib, niraparib, and talazoparib have recently been added to the armamentarium of drugs used for PC. There is no strong evidence of a clinically significant drug–drug interactions between PARP inhibitors and relugolix. However, some interactions may occur based on the metabolic pathways and enzyme inhibition properties of these drugs (Table 4). Olaparib and rucaparib moderately inhibit CYP3A4, which could increase relugolix plasma levels, potentially leading to enhanced testosterone suppression or an increased risk of adverse effects such as hot flashes and fatigue [44, 45]. Since niraparib has minimal CYP3A4 metabolism and talazoparib is not metabolized by CYP3A4 , neither is expected to interact with relugolix [46, 47] . None of the PARP inhibitors are CYP3A4 inducers, suggesting they do not accelerate relugolix metabolism. However, no clinical data have been reported for the coadministration of relugolix with PARP inhibitors.

Table 4.

A summary of the relationship between PARP inhibitors approved for prostate cancer and CYP3A4, and possible implications for coadministration with relugolix

PARP inhibitor	CYP3A4 substrate	CYP3A4 inhibitor	CYP3A4 inducer	Clinical implications	Possible interaction with relugolix
Olaparib	Major	Moderate	No	CYP3A4 inhibitors increase olaparib levels; CYP3A4 inducers decrease olaparib exposure.	May increase relugolix levels due to CYP3A4 inhibition.
Rucaparib	No	Moderate	No	Can increase plasma levels of CYP3A4-metabolized drugs.	Potential to slightly increase relugolix levels via CYP3A4 inhibition.
Niraparib	Minimal	Weak	No	Primarily metabolized by non-CYP enzymes (UGTs, carboxylesterases).	Unlikely to affect relugolix significantly.
Talazoparib	No	No	No	Eliminated largely unchanged in urine; minimal CYP metabolism.	No known CYP3A4 interaction with relugolix.

Conclusions

While relugolix in combination with ARPIs shows promise in the treatment of advanced prostate cancer, further research and real-world data will continue to inform the optimal use of relugolix in combination with ARPIs (Table 5). The combination of relugolix with ARPIs represents an evolving treatment strategy for advanced prostate cancer, offering a convenient oral regimen with rapid and sustained testosterone suppression. Real-world data and clinical trials suggest that coadministration with ARPIs does not compromise the efficacy of relugolix in maintaining castration levels, and dosing alterations are not required, although definitive confirmation from prospective, randomized studies is still needed. No new safety concerns have emerged. However, potential drug–drug interactions with CYP3A4 inducers such as apalutamide and enzalutamide require careful monitoring and possible dose adjustments. In contrast, abiraterone, a P-gp inhibitor, may increase relugolix concentrations, potentially enhancing its effects. Potential interactions of relugolix with PARP inhibitors, another class of medication that are increasingly used for the treatment of mPC, is low. Larger, prospective studies of relugolix with other systemic agents would be beneficial to provide clear guidance for the clinical practice.

Table 5.

Ongoing clinical trials with relugolix in combination with ARPIs [48]

Study title	NCT number	Phase
Comeback From Long coursE Androgen Deprivation Therapy (ADT) With RElugolix and Darolutamide (CLEARED)	NCT06463457	Phase 2
Neoadjuvant Darolutamide and Relugolix Combination Preceding Radical Prostatectomy for Prostate Cancer	NCT06631521	Phase 1
Relugolix + Enzalutamide Study in High-Risk Prostate Cancer	NCT06130995	Phase 1
REVELUTION-2: Relugolix+Abiraterone Acetate (AA) Versus Leuprolide+AA Cardiac Trial	NCT06650579	Phase 3
Relugolix and Enzalutamide in Combination With Radiation Therapy for the Treatment of Very High Risk Prostate Cancer, OPTIMAL Trial	NCT06499870	Phase 2
Stereotactic Body Radiation Therapy Plus Androgen Receptor Pathway Inhibitor and Androgen Deprivation Therapy for Treatment of Metastatic, Recurrent Hormone-Sensitive Prostate Cancer, DIVINE Trial	NCT06378866	Phase 2

Declarations

Funding

Open access publishing supported by the institutions participating in the CzechELib Transformative Agreement.

Conflict of interest

Tomas Buchler: Research support from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck KGaA, MSD, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol-Myers Squibb, AstraZeneca, Roche, Servier, Accord, MSD, and Pfizer. All unrelated to the present paper. Tomas Buchler is an Editorial Board member of Targeted Oncology. Tomas Buchler was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

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Authorship declaration

Review design, first draft, editing: Buchler.