SUMMARY  

• ERLEADA is an androgen receptor inhibitor. Patients on ERLEADA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy.¹ Relugolix is an oral GnRH receptor antagonist.² A dedicated drug-drug interaction study with ERLEADA and relugolix has not been reported.
• Apalutamide is primarily metabolized by CYP2C8 and CYP3A. Apalutamide is a strong inducer of CYP3A4, and a weak inducer of P-glycoprotein (P-gp). Apalutamide is also a moderate inhibitor of CYP2C8. Concomitant use of a medication that is a substrate of CYP3A4, P-gp, or other select proteins with apalutamide may result in loss of efficacy of this medication.¹
• Based on in vitro studies, relugolix is a substrate for CYP3A, CYP2C8, and P-gp. For additional information, please refer to the manufacturer of relugolix.²
• Relugolix substudy of the APA-RP study (NCT04523207): APA-RP was a phase 2, open-label, single arm, multicenter study that evaluated the efficacy and safety of adjuvant treatment with ERLEADA and androgen deprivation therapy (ADT) in treatment-naïve patients with high-risk localized prostate cancer who had undergone radical prostatectomy (RP; N=108).^3,4 A substudy evaluated sustained castrate serum testosterone levels (<50 ng/dL) with coadministration of ERLEADA 240 mg orally (PO) once daily (QD) and relugolix 120 mg PO QD (n=12). All patients who had serum testosterone measured at day 28 (n=11) maintained castrate levels (median 10.0 ng/dL) without relugolix dose adjustment.^5,6 In an update after one year of treatment, 10 patients receiving ERLEADA and relugolix maintained castrate serum testosterone levels (median 8.5 ng/dL) without dose modification of relugolix required. One month after treatment discontinuation, 8/10 patients experienced recovery (≥50 ng/dL) of their testosterone levels. Treatment-emergent adverse events (TEAEs) occurred in all 12 patients and were consistent with the known safety profiles for ERLEADA and relugolix.^7,8
• In a phase 1, open-label study that evaluated the safety and tolerability of ERLEADA 240 mg PO QD in combination with relugolix 240 mg PO QD in patients with advanced prostate cancer over 52 weeks (N=24), safety profiles were considered consistent with the individual drugs. TEAEs were reported in 87.5% of patients and the most common was rash (n=5). The mean testosterone level was below castration level at 15.3 ng/dL and the median prostate-specific antigen (PSA) level was 0.04 ng/mL through week 12. ERLEADA, N-desmethyl apalutamide, and relugolix concentrations were stable over 12 weeks indicating steady-state conditions.⁹
• Results have been reported from a real-world patient records review evaluating tolerability, safety, and pharmacodynamic outcomes of relugolix use in combination with androgen signaling inhibitors, including ERLEADA, in patients with advanced prostate cancer.¹⁰

PHARMACOKINETIC CONSIDERATIONS

Apalutamide is primarily metabolized by CYP2C8 and CYP3A.¹

In vitro and in vivo, apalutamide was identified as a CYP3A4 inducer. Apalutamide is also a moderate inhibitor of CYP2C8. Additionally, apalutamide is a weak inducer of P-gp.¹

Relugolix is a sensitive P-gp substrate and intestinal P-gp efflux is the primary determinant of relugolix absorption and oral bioavailability. Relugolix is metabolized through multiple pathways including CYP3A.²

Clinical Data

APA-RP Study

The APA-RP study evaluated the efficacy and safety of adjuvant treatment with ERLEADA and ADT in treatment-naïve patients with high-risk localized prostate cancer who had undergone RP (N=108).³

Study Design/Methods

• Phase 2, open-label, single-arm, multicenter study
• Patients underwent a perioperative screening period, 12-month main study, and a 12-month follow-up period with posttreatment follow-up every 6 months.
• During the main study, patients received ERLEADA 240 mg PO QD plus injectable ADT within 90 days post-RP for 12 cycles (28 days per cycle).
• Key inclusion criteria: candidates for RP or status (between days 29 and 90) post-RP (post-RP PSA ≤0.2 ng/mL within 90 days of surgery); histologically confirmed adenocarcinoma of the prostate categorized as high risk for recurrence (high risk defined as PSA ≥20 ng/mL, Gleason score [GS] ≥9 in any core, GS ≥8 [4+4 or 5+3] in >80% of 2 cores, or GS 8 [4+4 or 5+3] in 1 core if ≥5 other cores had a minimum GS of 4+3; criteria for high risk could have been met using biopsy or RP specimen); no prior treatment for prostate cancer; no evidence of metastatic prostate cancer; Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1  
• Key exclusion criteria: history or presence of soft tissue/bone metastasis or metastasis in distant lymph nodes (except pelvic lymph nodes below the iliac bifurcation with a short axis diameter of <2 cm determined radiographically or pathologically); history of bilateral orchiectomy; history of seizure or any condition or medication that may predispose to seizure; major adverse cardiac event within 12 months of enrollment; concomitant therapy for prostate cancer, including radiation therapy, during treatment or in the follow-up period
• Primary endpoint: Biochemical recurrence (BCR)-free survival at 24 months (12 months after completion of planned treatment)
  • BCR was defined as 2 sequential (measured within 3-4 weeks) PSA levels of >0.2 ng/mL
• Safety evaluations included the incidence of TEAEs through the day of the last dose + 30 days

Results

Patient Demographics

• Patient baseline demographic and disease characteristics can be found in Table: Select Patient Baseline Characteristics. A total of 82.0% of patients were White, 14.0% of patients were Black or African American, 3.7% of patients were Asian, and 0.9% of patients were of unknown race.
  • Overall, 85% (n=92) of patients received >11 treatment cycles, with none receiving >12 cycles.
  • Black (n=15) patients were younger than non-Black (n=93) patients (mean age, 58.4 vs 66.3 years), with a median preoperative PSA of 7.6 ng/dL (range, 2.2-62.7) and median baseline testosterone of 340.0 ng/dL (range, 43.0-939.0).¹¹ 

Efficacy

• Efficacy data results have been reported, however, results were not delineated for patients that received concomitant relugolix. The confirmed BCR-free rate at 24 months was 100% (90% CI, 93.0-100.0) in the modified intent-to-treat (mITT) population.
  • The mITT population included enrolled patients who met all eligibility criteria, received ≥1 dose of ERLEADA, had a baseline PSA, and ≥1 PSA value after treatment initiation.

Safety

• Safety data results have been reported, however, results were not delineated for patients that received concomitant relugolix. The most common any grade TEAEs were hot flush (69.0%), fatigue (54.0%), rash (21.0%), COVID-19 (18.0%), and arthralgia (17.0%). Additional rash-related safety data have been published, including a prespecified rash management guide outlining proactive steps for medical management of rash and patient education on gentle skin care implemented for patients enrolled in the study, with the intent to reduce the onset and severity of rash events.¹²

Relugolix Substudy

A total of 12 patients were also enrolled in a substudy evaluating concurrent ERLEADA and relugolix administration.⁵

Substudy Design/Methods

• Following RP, patients received relugolix 360 mg PO on day 14 then relugolix 120 mg PO QD on days -13 to -1. After confirmation of serum testosterone <50 ng/dL, patients received ERLEADA 240 mg PO QD plus relugolix 120 mg PO QD on days 1 to 28.
• Inclusion and exclusion criteria were the same as for the APARP main study.
• The primary endpoint was the percentage of patients maintaining castrate serum testosterone levels (defined as <50 ng/dL) through day 28. Serum testosterone was measured at days -14, 1, and 28.
• The secondary endpoint was safety, where TEAEs from days -14 to 28 were evaluated for relugolix monotherapy and ERLEADA and relugolix coadministration.

Results

Patient Demographics

• Patient baseline demographic and disease characteristics can be found in Table: Select Patient Baseline Characteristics.

Efficacy

• All patients received at least 1 dose of ERLEADA, and no patients discontinued during the substudy.
• At day 1, after 2 weeks of relugolix monotherapy, all 12 patients achieved castrate serum testosterone levels. Serum testosterone was measured for 11 patients at day 28 of ERLEADA and relugolix coadministration, and all 11 patients maintained castrate serum testosterone levels without requiring dose adjustment for relugolix. Serum testosterone levels measured can be seen in Table: Serum Testosterone Levels in the Relugolix Substudy.
• All 12 patients continued on to the APA-RP main study at cycle 2 day 1 and continued to receive ERLEADA and relugolix coadministration.
• In an update after 1 year of treatment, 1 patient withdrew from the study and 1 patient was noncompliant and subsequently withdrew from the study but maintained castration while on therapy. All of the 10 remaining patients maintained castrate serum testosterone levels, with no dose modifications for relugolix required.⁷ At 1 year, the median testosterone level was 8.5 ng/dL (range, 2.4-40.0). One month after treatment discontinuation, 8/10 patients experienced recovery (≥50 ng/dL) of their testosterone levels, with a median of 229.5 ng/dL (range, 23.0-352.0). The other 2 patients continue to be followed for testosterone recovery.⁸

Safety

• A total of 9 (75%) and 8 (67%) patients experienced TEAEs while receiving relugolix monotherapy and ERLEADA and relugolix coadministration, respectively (Table: Summary of TEAEs). TEAEs were consistent with the known safety profiles of ERLEADA and relugolix.

• In an update after 1 year of treatment, TEAEs occurred in all 12 patients and were consistent with the known safety profiles for ERLEADA and relugolix.⁷ Half were grade 3-4, 25% were considered serious, and 17% led to treatment discontinuation, interruption, or dose reduction. The most common TEAEs were fatigue and hot flash (42% each).⁸

Phase 1 Study

A phase 1, open-label study⁹ (NCT04666129) evaluated the safety and tolerability of ERLEADA or abiraterone acetate in combination with relugolix in patients with advanced prostate cancer over a 12-week primary treatment period and 40-week safety extension period. As part 1 of the study was focused on abiraterone acetate with prednisone or methylprednisolone plus relugolix, only results for part 2 are summarized below.

In part 2, patients received ERLEADA 240 mg PO QD and relugolix 240 mg PO QD. Of 24 enrolled patients, 20 completed the study. Patients were mostly White (67%) with a mean age of 69 years. The mean treatment adherence was >97% through week 52. Safety profiles with concomitant use were considered consistent with the individual drugs over 52 weeks. TEAEs were reported in 87.5% of patients, the majority were mild (grade 1-2), and the most commonly reported TEAE through week 52 was rash (n=5). The mean testosterone level was below castration level at 15.3 ng/dL and the median PSA level was 0.04 ng/mL through week 12. No relevant posttreatment changes in laboratory, ECG, or vital sign parameters were noted and drug concentrations were stable over 12 weeks, indicating steady-state conditions. ERLEADA, N-desmethyl apalutamide, and relugolix concentrations were stable over 12 weeks indicating steady-state conditions. Interim analysis results were previously reported.¹³ 

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 18 February 2025.