FormalPara Key Points

Relugolix at a standard dose maintained castrate levels of testosterone when coadministered with apalutamide.

Safety profiles of apalutamide and relugolix were similar to those reported previously for each drug.

1 Introduction

Localized prostate cancer (LPC) accounts for approximately 80% of PCs in the United States [1, 2], and an estimated 15–50% of patients with LPC are at high risk for recurrence [3, 4]. Treatment options for patients with high-risk (HR) LPC who are at high risk for local or distant recurrence include radical prostatectomy (RP) or radiation therapy (RT), alone or in combination with systemic therapies [5]. Recurrence occurs in up to 75% of high-risk patients who have undergone RP or RP/lymphadenectomy [6, 7]. Studies supporting adjuvant treatments with systemic therapies, such as gonadotropin-releasing hormone (GnRH) agonists or antagonists and androgen receptor (AR) signaling inhibitors, are limited, with a paucity of phase III trials [5, 6]. The combination of local therapies with systemic androgen-deprivation therapy (ADT) has been shown to benefit patients with node-positive PC [6]. Neoadjuvant abiraterone acetate plus prednisone added to ADT has been shown to suppress the androgen axis and thus improve pathologic outcomes in patients with HR-LPC undergoing RP [8]. More options for treatments with proven efficacy in high-risk disease, especially post RP, are an unmet clinical need.

Apalutamide is an orally available AR inhibitor that selectively blocks androgen-induced AR activation, prevents nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription [9]. Apalutamide decreases prostate cell proliferation, increases cell death in tumors [9], and, in combination with ADT, was approved by the US Food and Drug Administration for the treatment of nonmetastatic castration-resistant PC in 2018 and metastatic castration-sensitive PC in 2019 [10]. Apalutamide is currently being evaluated for the treatment of HR-LPC in two phase III studies, with RP and RT (PROTEUS and ATLAS, respectively) [11, 12].

Relugolix is an oral GnRH receptor antagonist that rapidly inhibits pituitary release of luteinizing hormone and follicle-stimulating hormone and has been shown to lower testosterone levels [13,14,15]. Relugolix was recently approved for treating patients with advanced PC based on results from the HERO study [16]. While relugolix is currently being evaluated in combination with other PC drugs, including apalutamide [17], the results have not yet been reported and there is a need to understand the effect of this combination on testosterone suppression.

Relugolix is metabolized through multiple pathways, including cytochrome P450 (CYP) 3A, and is a substrate of CYP2C8 and P-glycoprotein (P-gp) [16]. Intestinal P-gp efflux is the primary determinant of absorption and oral bioavailability of relugolix [16]. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp, as well as a moderate inhibitor of CYP2C9 [10]. The relugolix label recommends avoiding coadministration with combined P-gp and strong CYP3A inducers or, if unavoidable, to double the relugolix dose from 120 to 240 mg once daily [16]. However, no clinically significant differences in the pharmacokinetics of relugolix were observed when it was coadministered with other strong CYP3A inhibitors, such as voriconazole or enzalutamide [16]. Thus, it was hypothesized that relugolix administered concurrently with apalutamide should be able to maintain castrate levels of testosterone without modification of its dose.

The Apa-RP study (NCT04523207) is a single-arm, open-label, multicenter, phase II study evaluating the biochemical recurrence-free rate in patients with HR-LPC following RP who receive apalutamide with ADT. The primary hypothesis of the Apa-RP substudy is that castrate levels of serum testosterone (< 50 ng/dL) achieved following relugolix will be maintained after coadministration of relugolix with apalutamide 240 mg once daily, without the need to increase the maintenance dose of relugolix.

2 Patients and Methods

2.1 Study Design

The study design of the main study of apalutamide and ADT (Apa-RP) has been reported [18] and is described briefly above. The substudy was single arm and open label (Fig. 1) and enrolled 12 patients with HR-LPC from six community-based urology practices following an amendment of the original protocol on 20 April 2021. Eligibility criteria were the same as for the main study. Patients who were treatment naive, had no evidence of metastatic disease prior to substudy entry, were within 90 days post RP, and had prostate-specific antigen (PSA) ≤ 0.2 ng/mL at substudy entry were included. Patients had histologically confirmed adenocarcinoma of the prostate categorized as high risk for recurrent PC, which was defined as PSA ≥ 20 ng/mL or Gleason score (GS) ≥ 8 (≥ 9 in any core, or GS ≥ 8 [4 + 4 or 5 + 3] in > 80% of two cores, or GS = 8 [4 + 4 or 5 + 3] in one core with ≥ 5 other cores of GS ≥ 7). Reasons for exclusion from participation included history or presence of soft tissue/bone metastasis or metastasis in distant lymph nodes, history of bilateral orchiectomy, history of seizure or any condition or medication that may predispose to seizure, or major cardiovascular events within 12 months prior to baseline. Electronic Supplementary Table 1 provides a complete list of inclusion and exclusion criteria. All patients successfully completing the substudy were planned to transition to the main Apa-RP study, in which they would continue on relugolix + apalutamide. No pharmacokinetic assessments were planned in the substudy.

Fig. 1
figure 1

Schematic overview of the substudy. APA, apalutamide, RP radical prostatectomy, T testosterone

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2.2 Treatment

Patients received a loading dose of oral relugolix (360 mg) on Day − 14 followed by 2 weeks of 120 mg daily relugolix monotherapy, after which they were confirmed to have serum testosterone < 50 ng/dL, and then apalutamide (240 mg once daily) combined with relugolix (120 mg once daily) was administered for 28 days.

2.3 Efficacy Analysis

Efficacy assessments included serum testosterone measured at baseline (Day − 14; the first day of relugolix monotherapy), on the first day of apalutamide and relugolix coadministration (Day 1), and on Day 28 of apalutamide and relugolix coadministration. Testosterone < 50 ng/dL was considered castrate level [5]. The primary endpoint was the percentage of patients maintaining testosterone levels < 50 ng/dL through Day 28, and the secondary endpoint was safety.

2.4 Safety Analysis

Treatment-emergent adverse events (TEAEs) were evaluated from Days − 14 to 28 and were summarized for relugolix monotherapy and relugolix + apalutamide treatment periods. TEAEs were defined as any AE occurring at or after the initial administration of substudy intervention.

2.5 Statistical Analysis

The percentage of patients with testosterone < 50 ng/dL through Day 28 was summarized descriptively. The protocol dictated that the substudy would be considered negative if two or more participants had testosterone ≥ 50 ng/dL on Day 28. TEAEs were summarized descriptively. Events related to and associated with the recovery from the preplanned RP were not assessed.

3 Results

The substudy clinical data cut-off was 7 March 2022. The Apa-RP substudy enrolled 12 patients (median age 68 years) (Table 1). Median PSA at the time of initial diagnosis prior to RP was 7.4 (4.2–26.2) ng/dL. All 12 patients received one or more doses of apalutamide. The patient flow diagram is shown in Electronic Supplementary Fig. 1. No patients discontinued during the substudy period. All 12 patients received concomitant medication, most commonly lipid-modifying agents and analgesics (9 [75%] and 8 [67%], respectively) (see Electronic Supplementary Table 2).

Table 1 Baseline clinical and demographic characteristics
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All 12 patients achieved castrate testosterone levels after 2-week relugolix monotherapy (Fig. 2a). One patient inadvertently did not have testosterone measured at Day 28, but all 11 patients with available measurements maintained castrate testosterone levels at the end of apalutamide and relugolix coadministration without requiring adjustment of the relugolix dose. At baseline (Day − 14), median (range) serum testosterone was 348.5 (182–697) ng/dL; it decreased to 8.7 (< 3–26) ng/dL after 2 weeks of relugolix monotherapy and was 10.0 (< 3–35) ng/dL at Day 28 of apalutamide and relugolix coadministration (Fig. 2b).

Fig. 2
figure 2

Serum testosterone dynamics in the substudy from a subpopulation of evaluable patients with valid and non-missing testosterone values. Testosterone values collected as < 3.0 ng/dL or < 10 ng/dL were imputed to 2.9 ng/dL and 9.9 ng/dL, respectively, for median calculation. a Proportion of patients with castrate testosterone < 50 ng/dL at Days − 14, 1, and 28; b median testosterone levels (range) at Days − 14, 1, and 28; 50 ng/dL threshold, medians, interquartile ranges, and median ranges are shown. aOne patient had missing Day 28 testosterone measurement. bOne patient had missing Day 28 testosterone measurement. APA apalutamide

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TEAEs were reported in 9 (75%) patients while they were receiving relugolix monotherapy and in 8 (67%) patients while receiving relugolix + apalutamide treatment (Table 2), and were consistent with the known safety profiles of apalutamide and relugolix. All TEAEs were grade 1 or 2 (Electronic Supplementary Table 3). The most common TEAE was hot flush, which was grade 1, and occurred in 6 (50%) and 4 (33%) patients in the relugolix and relugolix + apalutamide treatment phases, respectively (Electronic Supplementary Table 3). Rash occurred in one (8.3%) patient treated with relugolix + apalutamide (Electronic Supplementary Table 3). No new safety signals were observed. No patients interrupted treatment, reduced their dose, or discontinued treatment due to TEAEs during the substudy period. All 12 patients transitioned to the main Apa-RP study and continued receiving relugolix + apalutamide. Efficacy and safety outcomes in these patients with longer follow-up will be reported together with the full cohort of the main study.

Table 2 Summary of treatment-emergent adverse events in the relugolix and relugolix + apalutamide treatment phases of the Apa-RP substudy
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4 Discussion

Recent research efforts to develop oral ADT led to the approval of relugolix, a nonpeptide GnRH receptor antagonist, for advanced prostate cancer. Whether relugolix effectively suppresses testosterone when administered concurrently with apalutamide has not yet been established and the clinical relevance of potential drug–drug interaction has not been addressed. The HERO study, which included 17 patients who were coadministered enzalutamide, demonstrated that relugolix at standard doses (360 mg loading dose followed by 120 mg daily) was sufficiently potent to lower testosterone to castrate levels [19]. It was hypothesized that administration of relugolix with apalutamide (a strong CYP3A inhibitor) may not lead to a clinically significant interaction. The Apa-RP substudy aimed to assess whether patients receiving concomitant apalutamide and relugolix were able to maintain castrate testosterone levels (< 50 ng/dL) without the need to adjust the relugolix dosing regimen. All patients achieved castrate testosterone levels after 2 weeks of relugolix monotherapy, and all patients with available data were able to maintain castrate testosterone while receiving relugolix + apalutamide. The safety profile of relugolix + apalutamide was consistent with the known adverse effects of these drugs [19,20,21,22,23]. All TEAEs were low grade, including the most common TEAE of hot flush, and none resulted in treatment discontinuation. All patients transitioned to the main study and continued receiving relugolix + apalutamide.

The recent National Comprehensive Cancer Network (NCCN) guidelines caution against using relugolix in combination with other commonly used agents in advanced PC because it has not been adequately studied [5]. The NCCN called for further investigations of relugolix dosing and drug–drug interactions to ensure proper dosing and safety. The guidelines also recommended ongoing monitoring for sustained suppression of testosterone (< 50 ng/dL) following relugolix due to uncertain patient compliance [5]. The relugolix prescribing information recommends doubling the relugolix dose from 120 to 240 mg once daily if coadministration with combined P-gp and strong CYP3A inducers is unavoidable [16].

Within the confines of the ongoing main Apa-RP study in community-based outpatient urology settings [18], additional visits for collecting pharmacokinetic samples from prostate cancer patients in this substudy were deemed not feasible. Despite the lack of formal pharmacokinetic assessments, it was not necessary for any substudy patients to double their relugolix dose to maintain castrate testosterone levels after the addition of apalutamide, suggesting a low probability of drug–drug interaction. Our results provide preliminary evidence that the standard dose of relugolix (120 mg) when taken once daily is sufficiently potent to consistently lower testosterone to castrate levels in the presence of apalutamide during the study duration. While other studies formally assessing the pharmacokinetics between apalutamide and relugolix are ongoing [24], our substudy provides the first evidence of the feasibility and efficacy of this combination.

No new safety signals were observed in this substudy compared with safety profiles of apalutamide and relugolix reported previously for each drug [19,20,21,22,23]. Similar to the findings in the HERO study, the most common AE was hot flush [19]. The incidence of skin rash during the short duration of the substudy was lower (8%) than previously reported in the SPARTAN and TITAN studies for advanced diseases (24–27%) [20,21,22,23]. Further information on patients who participated in the substudy, including long-term dermatological outcomes in these patients, will be available upon the completion of the main Apa-RP study. The safety and tolerability of relugolix + apalutamide are being investigated in an open-label study in patients with advanced PC for up to 1 year [17], and this may provide additional insights into this combination.

A limitation of this substudy was its open-label design and small sample size. Larger studies of relugolix and apalutamide are needed to confirm our observations. Despite the limitations, the substudy results are encouraging, and we look forward to future results on the combination of relugolix + apalutamide.

5 Conclusions

The results from this open-label, phase II evaluation of patients with HR-LPC post RP suggest that standard relugolix doses administered concurrently with apalutamide are effective at maintaining castrate levels of serum testosterone. In this study, the safety profile of relugolix + apalutamide was consistent with those previously reported for each drug.