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 sub-study of the APA-RP study (NCT04523207): APA-RP is a phase 2, open-label, single arm, multicenter study evaluating the efficacy and safety of the adjuvant treatment of ERLEADA and androgen deprivation therapy (ADT) in treatment-naïve patients with high-risk localized prostate cancer who have undergone radical prostatectomy (RP; N=108).^3-5 A sub-study evaluated sustained castrate serum testosterone levels (<50 ng/dL) with coadministration of ERLEADA and relugolix (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.^6,7 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.^8,9
• An ongoing, phase 1, open-label study (NCT04666129) is evaluating the safety and tolerability of ERLEADA in combination with relugolix in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-sensitive prostate cancer (mCSPC) over a 12-week primary treatment period and 40-week safety extension period. In an interim analysis, 10 patients with mCSPC received ERLEADA 240 mg daily and relugolix 360 mg as a single loading dose followed by 240 mg daily for a median of 180 days. No patients with nmCRPC were identified in the interim analysis. Two patients discontinued treatment during the safety extension period due to disease progression, and 1 patient discontinued treatment during the primary treatment period due to adverse events (AEs). A total of 28 non-serious AEs, including 2 grade 3-4 AEs, were reported in 8 patients. Of 28 AEs, 11 were considered by the investigator to be possibly or probably related to relugolix, with 12 possibly or probably related to ERLEADA. The most frequently reported AEs in 1 or 2 of 10 (≥10%) patients were pain in extremity, ALT increased, anemia, back pain, and vomiting. Median testosterone serum concentrations at baseline, week 5, and week 13 were 14.5 ng/dL, 15.0 ng/dL, and 14.0 ng/dL, respectively.¹⁰
• 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.¹¹

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

APA-RP is a study evaluating the efficacy and safety of the adjuvant treatment of ERLEADA and ADT in treatment-naïve patients with high-risk localized prostate cancer who have undergone RP (N=108).^3-5

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 post-treatment follow-up every 6 months.
• During the main study, patients received ERLEADA 240 mg by mouth (PO) daily (QD) plus ADT for 12 cycles (28 days per cycle).
• Key inclusion criteria: patients who were candidates for RP or between days 29 and 90 days post RP (recovery from RP; post RP prostate-specific antigen (PSA) ≤0.2 ng/mL); histologically confirmed adenocarcinoma of the prostate categorized as high risk for recurrent prostate cancer (defined as PSA ≥20 ng/mL, Gleason score [GS] ≥9 in any core on biopsy, GS ≥8 [4+4 or 5+3] in >80% of 2 cores on biopsy, or GS=8 [4+4 or 5+3] in 1 core as long as ≥5 other cores are with minimum GS of 4+3 on biopsy); 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; history of bilateral orchiectomy; history of seizure or any condition or medication that may predispose to seizure; cardiovascular risks within 12 months prior to baseline
• Primary endpoint: Biochemical recurrence (BCR)-free rate at 24 months (12 months after completion of treatment)
  • Confirmed BCR was defined as 2 sequential [measured within 3-4 weeks] PSA levels of >0.2 ng/mL
• Safety evaluations include incidence of TEAEs through the day of 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 81.5% of patients were White, 13.9% of patients were Black or African American, 3.7% of patients were Asian, and 0.9% of patients were of unknown race.

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 intention-to-treat population (mITT).
  • 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 (68.5%), fatigue (53.7%), rash (21.3%), COVID-19 (17.6%), and arthralgia (16.7%). Additional rash-related safety data have been published, including a pre-specified rash management guide implemented for patients enrolled in the study to improve dermatologic AEs with proactive steps for medical management of rash and patient education on gentle skin care outlined.¹²

Relugolix Sub-study

A total of 12 patients were also enrolled in a sub-study evaluating concurrent ERLEADA and relugolix administration.⁶

Sub-study 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 sub-study.
• 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 Sub-study.
• 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 one 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.⁸ At 1 year, the median testosterone level was 8.5 ng/dL (range, 2.4-40). 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, 23-352). The other 2 patients continue to be followed for testosterone recovery.⁹

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 one year of treatment, TEAEs occurred in all 12 patients and were consistent with the known safety profiles for ERLEADA and relugolix.⁸ 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).⁹

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 07 May 2024.