SUMMARY

• APA-RP (NCT04523207) 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).^1,2
  • The confirmed biochemical recurrence (BCR)-free rate at 24 months was 100% (90% CI, 93.0-100.0).¹
  • In a subgroup analysis, the confirmed BCR-free rate at 24 months was 100% in Black (90% CI, 57.9-100.0; n=15) and non-Black (90% CI, 93.1-100.0; n=93) patients.³
  • Treatment-emergent adverse events (TEAEs) were reported in 99% (n=107) of patients; 22% (n=24) were grade 3-4 in severity. The most common any-grade TEAEs were hot flush (69%), fatigue (54%), rash (21%), coronavirus disease 2019 (COVID-19; 18%), and arthralgia (17%).¹ Additional rash-related safety data, along with a prespecified rash management guide implemented to improve dermatologic AEs, have been published. The rash-related safety data were compared descriptively with the North American patient population of the global SPARTAN and TITAN studies.⁴ Results are summarized in Table: Rash-Related Safety Data Across the APA-RP, SPARTAN, and TITAN Studies.
  • A substudy evaluated sustained castrate serum testosterone levels (<50 ng/dL) with coadministration of ERLEADA and relugolix, an oral gonadotropin-releasing hormone antagonist (n=12). All patients who had serum testosterone measured at day 28 (n=11) maintained castrate levels (median 10 ng/dL) without relugolix dose adjustment.^5,6 In an update after 1 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. TEAEs occurred in all 12 patients and were consistent with the known safety profiles for ERLEADA and relugolix.^7,8

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).¹

Study Design/Methods

• Phase 2, open-label, single-arm, multicenter study
• Patients underwent a perioperative screening period, 12-month main study, and 12-month follow-up period with posttreatment follow-up every 6 months.
• During the main study, patients received ERLEADA 240 mg orally (PO) once daily (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 prostate-specific antigen [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: 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
• Secondary endpoints: BCR-free survival at 12 months (at the end of treatment); serum testosterone recovery rate to ≥50 ng/dL and ≥150 ng/dL at 18 and 24 months (6 and 12 months after the completion of adjuvant treatment with ERLEADA and ADT)
• Exploratory endpoints: impact of a proactive rash management guide on the incidence and severity of rash; unconfirmed BCR (defined as PSA >0.2 ng/mL detected in a single visit without confirmatory measurement)
• 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.
  • Overall, 85% (n=92) of patients received >11 treatment cycles, with none receiving >12 cycles.¹
  • 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).³

Efficacy

• Median follow-up duration was 21.4 months (range, 0.0-32.7).¹
• The confirmed BCR-free rate at 24 months was 100% (90% CI, 93.0-100.0) in the modified intent-to-treat (mITT) population.¹
  • 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.
  • The BCR-free rate at 12 months (at the end of treatment) was 100% (90% CI, 95.0-100.0).
  • The unconfirmed BCR-free rate at 24 months was 98% (90% CI, 92.0-100.0). Two patients had elevated PSA levels (PSA 0.39 ng/mL at 24 months and PSA 0.22 ng/mL at 30 months) just prior to the end of the study but confirmatory PSA measurements could not be obtained.
• Testosterone recovery was evaluated in a subset of patients (n=103) from the mITT population, who had ≥1 testosterone level measurement available after treatment completion. The serum testosterone recovery rate to ≥150 ng/dL at 6 and 12 months posttreatment were 36% (95% CI, 26.0-46.0) and 77% (95% CI, 66.0-85.0), respectively. The serum testosterone recovery rate to ≥50 ng/dL at 6 and 12 months posttreatment were 63% (95% CI, 52.0-72.0) and 96% (95% CI, 88.0-98.0), respectively.¹
• In a subgroup analysis of the mITT population, the confirmed BCR-free rate at 24 months in Black patients was 100% (90% CI, 57.9-100.0) and 100% (90% CI, 93.1-100.0) in non-Black patients. The unconfirmed BCR-free rate at 24 months in Black and non-Black patients was 100% (90% CI, 57.9-100.0) and 98.2% (90% CI, 91.1-99.7), respectively. The time to serum testosterone recovery (>150 ng/dL) event rate was 66.7% (n=10) in Black patients and 75.3% (n=70) in non-Black patients, with an 18 month event rate of 47.6% (95% CI, 14.8-74.9) and 41.3% (95% CI, 30.6-51.6), and a 24 month event rate of not estimable and 74.0% (95% CI, 62.3-82.5), respectively.³

Safety

• TEAE safety data from the APA-RP study are reported in Table: APA-RP Study Safety Data.

• Use of a prespecified rash management guide outlining proactive steps for medical management of rash and patient education on gentle skin care was implemented for patients enrolled in the study, with the intent to reduce the onset and severity of rash events. Rash-related safety data were collected during the first 12 months following initiation of ERLEADA treatment and compared descriptively with the North American patient populations of the global SPARTAN and TITAN studies.⁴ Results can be found in Table: Rash-Related Safety Data Across the APA-RP, SPARTAN, and TITAN Studies.

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%) of 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

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 05 August 2024.