SUMMARY

• ATLAS (NCT02531516) is an ongoing phase 3, randomized, double-blind, placebocontrolled, multicenter study evaluating the efficacy and safety of adding ERLEADA to gonadotropin-releasing hormone agonist (GnRHa) and external beam radiation therapy (EBRT) in patients with high-risk localized or locally advanced prostate cancer. The primary endpoint is metastasis-free survival (MFS). Currently, the study is fully enrolled. Safety and efficacy results have not been published.^1-3
• PROTEUS (NCT03767244) is an ongoing phase 3, randomized, double-blind, placebocontrolled, multicenter study evaluating the efficacy and safety of ERLEADA plus androgen deprivation therapy (ADT) compared to placebo plus ADT before and after radical prostatectomy (RP) in patients with localized or locally advanced high-risk prostate cancer. The dual primary endpoints are pathologic complete response (pCR) rate and MFS. The study is expected to enroll approximately 2000 patients from >203 sites in 18 countries. Safety and efficacy results have not been published.^4,5
• ARNEO (NCT03080116) was a phase 2, randomized, double-blind, placebo-controlled single-center study that evaluated the pathological outcomes of degarelix with or without ERLEADA before RP in patients with high-risk prostate cancer. The minimal residual disease (MRD) rate in patients who received degarelix plus ERLEADA vs degarelix plus placebo was 38% vs 9.1% (RR, 4.16; 95% CI, 1.5211.4; P=0.002). Neoadjuvant treatment was well tolerated in both arms with no grade 4-5 treatment-related adverse events (TRAEs) reported. Grade 3 rash was reported in 4 (8.9%) patients in the degarelix plus ERLEADA arm.⁶ Results from 3-year efficacy⁷ and 2-year quality of life (QoL) follow-up⁸ analyses have been published.
• A phase 2 study evaluated the pathologic and imaging response to neoadjuvant ADT with abiraterone acetate plus prednisone (AAP) or AAP with ERLEADA (A-AAP) before RP in patients with high-risk localized prostate cancer (HRLPC; N=62). Rate of pCR or MRD in patients who received AAP vs A-AAP was not statistically significantly different (3% vs 7%, respectively). Grade 3-4 TRAEs were reported in 9 (14.5%) patients (A-AAP, n=6; AAP, n=3), and the most common grade 34 adverse events (AEs) were hypertension (11.3%), aspartate transaminase (AST)/alanine transaminase (ALT) elevations (3.2%), and skin rash (1.6%).^9,10
• A phase 2 study evaluated pathological outcomes of neoadjuvant ERLEADA before RP in patients with intermediate or high-risk prostate cancer (N=30). Of the 25 patients that underwent RP, 84% of patients achieved post-prostatectomy nadir prostatespecific antigen (PSA) levels (<0.03 ng/mL). No patient experienced a pCR. Common AEs included dry skin (n=16; 53.3%), fatigue (n=10; 33.3%), and skin rash (n=9; 30.0%). One patient experienced an unrelated grade 3 AE, and no patients experienced a Clavien-Dindo grade ≥3 surgical complication.^11-14
• A phase 2 study evaluated the clinical effects of neoadjuvant treatment with ERLEADA in combination with AAP, degarelix, and indomethacin in patients with high- to very high-risk prostate cancer (N=20). At RP, 1 (5%) patient achieved pCR and 6 (30%) patients had MRD. Treatment was generally well tolerated, and AEs were consistent with the known safety profile of the study drugs.^15,16
• AASUR (NCT02772588) is an ongoing phase 2 study in very high-risk patients with node negative prostate cancer (N=64) treated with ERLEADA plus abiraterone acetate and prednisone plus leuprolide (A-APL) and ultrahypofractionated radiation therapy (UHRT). Interim results reported a 3-year biochemical recurrence-free survival (bRFS) of 89.7%, rapid recovery of non-castrate testosterone levels, and limited toxicities.^17,18
• Results from a phase 2 study evaluating neoadjuvant treatment with either A-APL or AAP and leuprolide (APL) before RP in patients with HRLPC (N=118) have been reported. In part 1 of the study, the centrally assessed pCR or MRD rate in patients who received A-APL and APL was 22% and 20%, respectively (1-sided 95% CI, 11%14%; 1-sided P=0.4). Grade 3 TRAEs in the A-APL and APL arms were reported in 8 and 5 patients, respectively, with no grade 4 or 5 TRAEs reported.¹⁹ From part 1, 69% of patients were enrolled in part 2 of the study. Patients who achieved pathologic responses (n=14) had longer biochemical progression-free survival (PFS) than nonresponders (3-year biochemical PFS, 100% vs 72%; log-rank test 2-sided P=0.03).²⁰
• APA-RP (NCT04523207) is a phase 2, open-label, single-arm, multicenter study evaluating the efficacy and safety of the adjuvant treatment of ERLEADA and ADT in treatment-naïve patients with HRLPC who have undergone RP (N=108).^21-23 The confirmed biochemical recurrence (BCR)-free rate at 24 months was 100% (90% CI, 93.0-100.0). The most common any-grade treatment-emergent adverse events (TEAEs) were hot flush (68.5%), fatigue (53.7%), rash (21.3%), coronavirus disease 2019 (COVID-19; 17.6%), and arthralgia (16.7%).²¹ Additional rash-related safety data, along with a pre-specified rash management guide implemented to improve dermatologic AEs, have been published.²⁴ Additionally, results from a substudy evaluating sustained castrate serum testosterone levels (<50 ng/dL) with coadministration of ERLEADA and relugolix^25-28 and a subgroup analysis of Black and non-Black patients²⁹ have been published.
• Interim analyses from 2 additional phase 2 studies have been published.^30-32 Results from a phase 2 study that included patients with multiple clinical states of prostate cancer have been published, however, results were not delineated for patients with high-risk, localized or locally advanced prostate cancer.^33,34 Additionally, results related to tumor pathology measures from a phase 2 study have been published.³⁵

CLINICAL DATA

Phase 3 Studies

ATLAS Study

ATLAS is an ongoing study evaluating the efficacy and safety of adding ERLEADA to GnRHa and EBRT in patients with high-risk localized or locally advanced prostate cancer.^1-3

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multicenter study
• Currently, the study is fully enrolled.
• A total of 1503 patients were randomized 1:1 to receive the treatments described in Figure: ATLAS: Study Design during each 28-day treatment cycle.^1-3

• Long-term follow-up will consist of monitoring PSA and testosterone levels every 3 months until distant metastasis by blinded independent central review (BICR), conventional imaging every 6 months until distant metastasis by BICR or death, and positron emission tomography (PET) imaging every 6 months until distant metastasis on PET or conventional imaging by BICR or death.
• The collection of PET imaging data was added to the protocol to guide treatment of patients with biochemical failure (BCF) or progressive disease after definitive radiation therapy (RT) and hormonal therapy.
• The safety evaluation is based on periodic physical examination, vital signs, and laboratory tests at clinic visits.
• The effect of adding ERLEADA to GnRHa on symptoms, function, and health-related quality of life (HRQoL) will be evaluated via patient-reported outcomes (PROs).

Results

Patient Characteristics

• The demographics and baseline characteristics of all patients enrolled in the ATLAS study are described in Table: Select Patient Baseline Characteristics.
• A total of 90% of patients received standard EBRT to the prostate/pelvis over 68 weeks, while 10% and 6% of patients received hypofractionation and EBRT combined with brachytherapy, respectively.
• Patient retention and physician engagement strategies were initiated during the COVID-19 pandemic, and a 96% patient retention rate was observed.³⁶

PROTEUS Study

PROTEUS is an ongoing study evaluating the safety and efficacy of ERLEADA plus ADT compared to placebo plus ADT before and after RP in patients with localized or locally advanced high-risk prostate cancer.^4,5

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multicenter study
• Approximately 2000 patients from >203 sites in 18 countries will be randomized 1:1 to receive treatment with ERLEADA or placebo plus ADT. The study design is described in Figure: PROTEUS: Study Design.^4,5

• Conventional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) and bone scan will be conducted at baseline, within 4 weeks after RP, at BCF (defined as 2 consecutive PSA rises with the second consecutive test resulting in an absolute PSA value of ≥0.2 ng/mL), and then every 6 months following BCF until distant metastasis is documented by BICR or death.
• PSA testing and radiological assessment for progression is permitted in the neoadjuvant setting (cycles 1-6).
• Adjuvant or salvage RT post RP may be performed at the discretion of the investigator (cycles 7-12).
• The total time to final analysis is estimated to be 7.5 years (3 years accrual and
  4.5 years follow-up).

Phase 2 Studies

Devos et al (2023)⁶ reported results from ARNEO, a phase 2 study that compared the efficacy and safety of neoadjuvant degarelix plus ERLEADA vs degarelix plus placebo before RP in patients with highrisk prostate cancer (N=89).

Study Design/Methods

• Phase 2, randomized, double-blind, placebo-controlled, single-center study
• Patients were randomized 1:1 to receive either neoadjuvant degarelix (240-80-80 mg) plus ERLEADA (240 mg/day) or degarelix (240-80-80 mg) plus placebo for 3 months followed by RP plus extended pelvic lymph node dissection (ePLND).
• Select inclusion criteria: unfavorable intermediate-risk (defined as ≥2 of the following factors: Gleason Score [GS] 7, PSA 10-20 ng/mL, and/or clinical stage T2b [cT2b]) or high-risk prostatic cancer (GS 8-10, PSA >20 ng/mL, ≥cT2c, and/or cN1 disease); amenable to RP plus ePLND
• Select exclusion criteria: patients with cM1 disease; neuroendocrine differentiation or small cell features on prostate biopsy; Eastern Cooperative Oncology Group performance status (ECOG PS) >1; active treatment with medication known to influence PSA; previous surgical/endoscopic treatments for prostate disease; history of prior malignancy within 5 years prior to randomization
• Primary endpoint: difference in proportion of patients with MRD (residual cancer burden [RCB] ≤0.25 cm³)
• Secondary endpoints: differences in PSA response; pathological response; change in TNM stage on prostate-specific membrane antigen (PSMA) PET/MRI following hormonal treatment; AEs; surgical safety (Clavien-Dindo classification); QoL questionnaires (International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form [ICIQ-UI], International Index of Erectile Function [IIEF-5], and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30])
• Exploratory endpoints: biomarkers associated with pathological response (MRD and RCB)

Results

Patient Characteristics

• A total of 89 patients were randomized to the neoadjuvant degarelix plus ERLEADA (n=45) or degarelix plus placebo (n=44) arm for 12 weeks and underwent RP.
• Baseline characteristics were balanced between treatment arms. In both arms, 98% of patients had high-risk disease.
• Median PSA at the time of biopsy in the degarelix plus ERLEADA and degarelix plus placebo arms were 12.6 ng/mL (interquartile range, [IQR], 7.8-19.7) and 11.2 ng/mL (IQR, 8.1-19.3), respectively.

Efficacy

• The MRD rate in patients who received degarelix plus ERLEADA vs degarelix plus placebo was 38% vs 9.1% (RR, 4.16; 95% CI, 1.52-11.4; P=0.002). Pathological outcomes are described in Table: Pathological Outcomes at RP.
• The median pre-RP PSA nadir in the degarelix plus ERLEADA vs degarelix plus placebo arm was 0.11 ng/mL vs 1.20 ng/mL (HL∆, 1.06 ng/mL; 95% CI, 0.74-1.59 ng/mL; P<0.001).
  • The rate of patients reporting a pre-RP PSA nadir <0.3 ng/mL was 87% in the degarelix plus ERLEADA arm, compared with 9.1% of patients in the degarelix plus placebo arm (RR, 9.53; 95% CI, 3.72-24.4; P<0.001).
  • At 6 months following surgery, 93% of patients in the degarelix plus ERLEADA arm and 96% of patients in the degarelix plus placebo arm were free from BCR.
• Following neoadjuvant treatment, a total of 18 (40%) patients in the degarelix plus ERLEADA arm and 13 (30%) patients in the degarelix plus placebo arm experienced T downstaging (RR, 1.35; 95% CI, 0.76-2.42; P=0.3). In both treatment arms, 6 (13%) patients experienced cN downstaging.
• When compared with the degarelix plus placebo arm, patients in the degarelix plus ERLEADA arm had significantly lower PSMA PET-estimated volume (1.3 vs 3.1 mL; HL∆, 1.45 mL; 95% CI, 0.48-2.60 mL; P=0.003) and PSMA PET maximum standardized uptake value (SUV_max) (4.2 vs 6.5; HL∆, 2.11; 95% CI, 1.22-3.27; P=0.001).
• Exploratory endpoints associated with MRD and RCB:
  • When compared with patients without PTEN loss, patients with PTEN loss at baseline prostate biopsy achieved a lower MRD (43% vs 11%; RR, 0.25; 95% CI, 0.1-0.63; P=0.002) and higher RCB at final pathology (0.40 vs 1.6 cm³, HL∆, 1.16 mL;
  • 95% CI, 0.50-4.28 mL; P<0.001).
  • Following neoadjuvant treatment, PSMA PET-estimated volume and PSMA PET SUVmax were lower in patients with MRD than in patients without MRD (1.2 vs 2.5 mL, HL∆, 1.22 mL; 95% CI, 0.26-2.84 mL; P=0.01 and 4.3 vs 5.7, HL∆, 1.6; 95% CI, 0.45-3; P=0.007, respectively).
  • Following neoadjuvant treatment, PSMA PET-estimated volume and PSMA PET SUVmax correlated moderately with RCB at final pathology (both P<0.001).
• No major differences were observed between both groups in terms of surgery-related characteristics, QoL, urinary incontinence, and erectile function at baseline, following neoadjuvant treatment, and at 6 weeks following RP.

Safety

• Overall, neoadjuvant treatment was well tolerated in both arms.
• No grade 4-5 TRAEs were reported.
• Grade 3 rash was reported in 4 (8.9%) patients in the degarelix plus ERLEADA arm.
• One serious TRAE (drug-induced interstitial lung disease) was reported in the degarelix plus ERLEADA arm during neoadjuvant treatment.

3-Year Efficacy Follow-Up

Devos et al (2024)⁷ reported results from a 3-year follow-up of ARNEO that compared the oncological outcomes of neoadjuvant degarelix plus ERLEADA vs degarelix plus placebo before RP in patients with highrisk prostate cancer.

Study Design/Methods

• Patients receiving degarelix plus ERLEADA were matched to patients treated with surgery alone (in the same center during the same period) and included in the survival analyses as part of a standard of care (SOC) control arm.
• PSA and testosterone testing were conducted every 6 months, and no adjuvant RT or hormonal therapy was given.
  • Patients undergoing PSA relapse underwent PSMA-PET/CT scan. In case of negative imaging outcomes, they received salvage RT to the prostate bed and if required, to the pelvic region.

Results

• At a median follow-up of 34 months (IQR, 26-40) for degarelix plus ERLEADA and 32 months (IQR, 27-38) for degarelix plus placebo, the median time to testosterone recovery was 6 months in both arms.
• The BCR rate was 22% (n=10) for degarelix plus ERLEADA and 36% (n=16) for degarelix plus placebo (P=0.14).
  • At the final pathological assessment, there was no statistically significant difference in BCR rate between patients with and without MRD (both 29%; P=0.94).
  • The presence of ypT2 disease was significantly associated with improved BCR-free survival (9% vs 43%; P=0.001).
• The metastatic disease rate was 2.2% (n=1) for degarelix plus ERLEADA and 14% (n=6) for degarelix plus placebo (P=0.04).
• At a median follow-up of 36 months (IQR, 30-44) in the SOC arm (n=38), no patients developed metastatic disease in the matched degarelix plus ERLEADA arm (n=38) compared to 11% (n=4) of patients in the SOC arm who developed metastasis (P=0.04).

2-Year QoL Follow-Up

Giesen et al (2024)⁸ reported results from a 2-year follow-up of ARNEO that compared QoL using ICIQ-UI, IIEF-5, and EORTC QLQ-C30 scores associated with neoadjuvant degarelix plus ERLEADA vs degarelix plus placebo before RP in patients with highrisk prostate cancer.

Study Design/Methods

• The ICIQ-UI, IIEF-5, and EORTC QLQ-C30 questionnaires were completed before starting neoadjuvant treatment, after 12 weeks of treatment, after surgery, and annually thereafter for 3 years.

Results

• Median QLQ scores were reported for different time points: at inclusion, prior to RP, post-RP, 1 year post-RP, and 2 years post-RP.
• Median ICIQ-UI scores (range, 0-21) at different time points for patients receiving degarelix plus placebo vs degarelix plus ERLEADA were 0 vs 0, 0 vs 0, 10.5 vs 9, 4 vs 3, and 5 vs 3, respectively. There were no significant differences between the 2 arms at any time point (P>0.3).
• Median IIEF-5 scores (range, 5-25) at different time points for patients receiving degarelix plus placebo vs degarelix plus ERLEADA were 7 vs 6, 1 vs 1, 1 vs 1, 2 vs 2, and 1 vs 2, respectively. There were no significant differences between the 2 arms at any time point (P>0.08).
• Median EORTC QLQ-C30 scores (range, 0-100) at different time points for patients receiving degarelix plus placebo vs degarelix plus ERLEADA were 83.3 vs 83.3, 75 vs 87.5, 75 vs 75, 83.3 vs 83.3, and 75 vs 83.3, respectively. There were no significant differences between both the 2 arms (P>0.17), except for the global health score at inclusion (P=0.04).

Bastos et al (2022)⁹ reported results from a phase 2 study that evaluated the pathologic and imaging response to AAP or A-APA before RP in patients with HRLPC (N=62).

Study Design/Methods

• Phase 2, investigator-initiated, randomized study
• Patients were randomized 1:1 to receive either single-dose neoadjuvant ADT 10.8 mg subcutaneously (SC) on day 1 plus abiraterone acetate 1000 mg/day plus prednisone
• 5 mg twice daily (AAP arm; n=31) or AAP with ERLEADA 240 mg/day (A-AAP arm; n=31) for 3 months in 28-day cycles prior to RP.¹⁰
• Primary endpoint: rate of pCR or MRD (tumor ≤0.5 cm)
• Secondary endpoints: safety, rate of RCB ≤0.25 cm³ (RCB=tumor volume × cellularity), gallium 68 PSMA-PET/magnetic resonance correlates, and rate of biochemical relapse (BR)

Results

Patient Characteristics

• A total of 62 patients were randomized to the AAP (n=31) or A-AAP (n=31) arm.
• The median age was 65 years (range, 47-77).
• Risk groups categorized by National Comprehensive Cancer Network (NCCN) included 19% of patients with high-risk disease, 76% of patients with very high-risk disease, and 5% of patients with regional (N1) disease (cT3, 79%; GS 8-10, 65%; PSA ≥20 ng/mL, 57%).

Efficacy

• There was no statistically significant difference in pCR/MRD or RCB ≤0.25 cm³ rate between the study arms (Table: Pathological Outcomes After Neoadjuvant Therapy).
• RCB ≤0.25 cm³ rate in patients with a complete PSMA-PET response (psmaCR) and without psmaCR was 50% and 7.5%, respectively (P=0.001).
• The rate of BR in patients with RCB ≤0.25 cm³ and >0.25 cm³ was 14% and 38%, respectively (P=0.118).
• At a median follow-up of 2.6 years, all patients with both psmaCR and RCB ≤0.25 cm³ (n=11 [18%]) were free of BR.

Safety

• There were 2 grade 5 AEs in the AAP arm (pulmonary embolism [PE] and sudden death, both after surgery).
• Grade 3-4 TRAEs were reported in 9 (14.5%) patients (A-AAP, n=6; AAP, n=3), and the most common grade 3-4 AEs were hypertension (11.3%), AST/ALT elevations (3.2%), and skin rash (1.6%).
• An additional study examined the perioperative complication rates after RP in this HRLPC patient population which received neoadjuvant therapy (neoadjuvant arm, n=61) in comparison with HRLPC patients without prior neoadjuvant therapy (control arm, n=63).³⁷
  • Clavien-Dindo grade ≥3 major surgical complications were reported in 4 (6.6%) patients in the neoadjuvant arm and 5 (7.9%) patients in the control arm at ≤30 days of surgery (Table: Perioperative Complications at ≤30 Days of Surgery).
  • A total of 64% of patients in the neoadjuvant arm and 22% of patients in the control arm received thromboprophylaxis for 28 days.
  • The study reported 2 (4.9%) cases of thromboembolic events in the neoadjuvant arm within ≤30 days after surgery.
  • There were 2 deaths reported in each arm, of which, 1 death in the neoadjuvant arm was from possible PE.
    • After the first thromboembolic event was identified in the study, a protocol amendment was made to mandate prophylactic anticoagulation therapy after surgery to all patients, except in cases of major contraindication.

Lee et al (2022)¹² reported results from a phase 2 study evaluating pathological outcomes of neoadjuvant ERLEADA before RP in patients with intermediate or high-risk prostate cancer (N=30).

Study Design/Methods

• Phase 2, open-label, single-arm study
• Patients received ERLEADA 240 mg orally (PO) daily for 12 weeks followed by RP within 6 weeks of the last dose of medication.
• Select inclusion criteria: newly-diagnosed adenocarcinoma of the prostate; D’Amico intermediate or high-risk prostate cancer; absence of nodal and distant metastases; normal liver and thyroid function
• Select exclusion criteria: small cell, neuroendocrine, or ductal variants; prior pelvic radiotherapy; radio-recurrent disease; renal impairment and serum creatinine >2x upper limit of normal (ULN); ECOG PS of ≥2
• Primary endpoint: pCR rate at the time of RP
• Secondary endpoints: biochemical response rate (defined as PSA levels <0.03 ng/mL at week 24), pathological response rate (defined as change in tumor burden), tissue response (groups A-C, with C being the least favorable response), TRAEs, and perioperative complication rates following RP

Results

Patient Characteristics

• At diagnosis, the median age was 68.6 years old and median serum PSA was 12.8 ng/mL.
• A total of 10 (33.3%) and 20 (66.7%) patients had D’Amico intermediate-risk and highrisk prostate cancer, respectively.
• Patients had an International Society of Urological Pathology (ISUP) grade group of 1 (n=1 [3.3%]), 2 (n=13 [43.3%]), 3 (n=11 [9.0%]), 4 (n=3 [10.0%]), and 5 (n=2 [6.7%]).

Efficacy

• The median duration of follow-up was 36.7 months (IQR, 31.140.0 months) at the time of analysis.
• A total of 25 patients underwent RP per protocol and were included in the efficacy and safety analysis.
• No patient experienced a pCR.
• The post-therapy morphology classifications included 11 (44.0%) group A patients, 7 (28.0%) group B patients, and 7 (28.0%) group C patients.
• Post-prostatectomy nadir PSA levels were achieved in 84% of patients, and the remainder of patients achieved nadir PSA levels of 0.03-0.05 ng/mL.¹¹
• A total of 4 patients did not achieve PSA <0.3 ng/mL. Of the remaining 21 patients that achieved PSA<0.3 ng/mL, 3 patients experienced a BR.
• After treatment with neoadjuvant ERLEADA alone, the median reduction of serum PSA was 97.3% (range, 61.2-100.0; P<0.0001).¹¹

Patient-Reported HRQoL

• Patient-reported HRQoL outcomes were evaluated at weeks 0, 4 and 12 using the EORTC QLQ-C30, EORTC Quality of Life Questionnaire Prostate Module (QLQ-PR25), and Sexual Health Inventory for Men (SHIM).
• There were no clinically significant changes observed in the overall health scores across 12 weeks of neoadjuvant ERLEADA treatment (n=29; change in mean score, -3.5; P=0.33)
• Reduced cognitive function (P=0.038), role functioning (P=0.025), sexual function (P<0.001) and increased fatigue (P=0.012) were observed.¹⁴

Safety

• TRAEs were reported in 93.3% (n=28) of patients; the most common AEs were dry skin (n=16; 53.3%), fatigue (n=10; 33.3%), and skin rash (n=9; 30.0%).
• Dose modification of ERLEADA was required to manage TRAEs in 7 patients (rashes, n=5; dry skin, n=1; concurrent upper respiratory tract infection, n=1).¹³
• One patient experienced an unrelated grade 3 AE.¹¹
• Clavien-Dindo grade 1-2 surgical complications were experienced by 5 (20%) patients who underwent RP.
  • No patients experienced a Clavien-Dindo grade ≥3 surgical complication.¹³

Graham et al (2021)¹⁵ reported results from a phase 2 study evaluating the clinical effects of neoadjuvant indomethacin, in addition to combinational antiandrogen blockade, in men with localized high to very-high-risk prostate cancer undergoing RP (N=20; NCT02849990).¹⁶

Study Design/Methods

• Phase 2, open-label, single site trial
• Eligible men had localized, surgically resectable, high- to very-high-risk prostate adenocarcinoma.
• Patients received 12 weeks of neoadjuvant therapy with 3 times daily indomethacin 50 mg combined with ERLEADA, abiraterone acetate, and degarelix at their respective Food and Drug Administration (FDA)-approved doses plus prednisone 5 mg twice daily followed by RP.
• Select inclusion criteria: histologically confirmed adenocarcinoma of the prostate; high-risk (GS 8-10 or T3a or PSA >20 ng/mL); or very high-risk prostate cancer (T3bT4); ECOG PS of ≤2; serum testosterone ≥150 ng/dL¹⁶
• Select exclusion criteria: prior local therapy for prostate cancer (eg, RP, RT, brachytherapy); prior or ongoing systemic therapy for prostate cancer; clinically significant cardiovascular conditions; pre-existing viral hepatitis or hepatic impairment (Child-Pugh class B or C); seizure or any condition that may predispose to seizure¹⁶
• Primary endpoint: pCR rate (defined as the absence of visible tumor by hematoxylin and eosin-stained slides)
• Select secondary endpoints: MRD (defined as RCB ≤0.25 cm³), PSA PFS (defined as a value of ≥2 ng/mL confirmed on 2 consecutive measurements), and MFS (defined as visible lesions on bone scan, CT, or PET)

Results

Patient Characteristics

• Of the 22 patients enrolled in the study, 20 were evaluable for the primary endpoint
  (1 patient discontinued to pursue stereotactic radiosurgery and 1 patient discontinued due to grade 3 transaminitis).
• The median baseline PSA was 10.2 ng/mL (range, 4.4-159.4).
• Four patients (20%) had Gleason grade 4 and 16 (80%) patients had Gleason grade 5.
• The median age at diagnosis was 63 years (range, 61-73).

Efficacy

• One (5%) patient had a pCR, which was identical to the null hypothesized value.
• Six (30%) patients had MRD, for an overall pathologic response rate of 35%.
  • Four of these patients had ypT3 disease at the time of surgery.
• Eighteen (90%) patients had ypT3 stage at RP and 7 (35%) had lymph node metastases.
• Eight patients had adjuvant radiation following RP.
• Over a median follow-up for PSA relapse of 23.8 months (IQR, 20.3-26.9 months), 1 of 7 (14%) men with pathologic response and 6 of 13 (46%) men without pathologic response had a PSA relapse (P=0.3).
• Over a median follow-up for metastasis of 24.8 months (IQR, 21.4-32.6 months), 1 of 7 (14%) patients with a pathologic response and 1 of 13 (8%) patients without a pathologic response developed metastasis (P=0.7), both of whom also had PSA relapses.

Safety

• Treatment was well tolerated with AEs consistent with each drug’s safety profile.

McBride et al (2021)¹⁷ reported results from the AASUR study, an ongoing phase 2 study in very high-risk patients with node negative prostate cancer treated with A-APL in conjunction with UHRT (N=64).¹⁸

Study Design/Methods

• Phase 2, open-label, single-arm study¹⁸
• Patients received 6-month treatment with ERLEADA in combination with¹⁷:
  • Abiraterone and prednisone plus
  • Leuprolide with UHRT 7.5-8 Gy x 5 fractions
• Select inclusion criteria: very high-risk prostate cancer defined as having a GS of 910, or >4 cores of GS 8 disease, or 2 high-risk features (including rT3/T4 disease)
• Select exclusion criteria: radiographic evidence of metastatic disease, severe hepatic impairment (Child-Pugh Class C), and prior treatment for prostate cancer except for patient who received luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy for ≤1 month prior to study enrollment.¹⁸
• Primary endpoints: BCR defined as nadir PSA + 2 ng/mL.¹⁷

Results

Patient Characteristics

• The median age was 69 years old (range, 50-90) and serum PSA at baseline was 12 ng/dL (range, 3.1-209.5).
• A total of 70.3% of patients (45/64) had a GS of 9-10, 21.9% (14/64) had a GS of 8, and 7.8% (5/64) had a GS of 6-7.
• At diagnosis, the radiographic T stages (MRI technique) were as follows: T2, 70.3% (45/64); T3a, 18.7% (12/64); T3b, 10.9% (7/64).

Efficacy

• A total of 98.4% of patients (63/64) achieved an undetectable nadir PSA.
  • The median time to nadir PSA from start of treatment was 2 months (range, 1-9).
• The median time to achieve the post-treatment, non-castrate testosterone level (>150 ng/mL) was 6.5 months (range, 2.5-25.5).
• BCR was reported in 7 patients.
• The 2- and 3-year bRFS were 95% (95% CI, 89.7-100) and 89.7% (95% CI, 81-99.3), respectively.
• Among the 57 patients without BCR (median follow-up of 30 months), 98.2% (56/57) had a non-castrate testosterone concentration of >150 ng/mL at the last follow-up visit.
  • The median PSA was 0.10 ng/mL (IQR, <0.10-0.30).
    • PSA of ≤0.20 ng/mL was reported in 70.2% of patients (40/57).
    • Undetectable PSA (<0.10 ng/mL) was reported in 42.1% of patients (24/57).

Safety

• Transient grade 3 toxicities were reported in 15 patients (hypertension, n=12; rash, n=3).

McKay et al (2021)¹⁹ and (2024)²⁰ reported results from part 1 and part 2 of a phase 2 study evaluating the effect of intense neoadjuvant hormone therapy before RP on pathologic response in patients with HRLPC (N=118; NCT02903368).

Study Design/Methods

• Phase 2, randomized, open-label, multicenter study
• In part 1 of the study, patients were randomized (1:1) to receive either ERLEADA 240 mg PO once daily (QD) in combination with abiraterone acetate 1000 mg PO QD plus prednisone 5 mg PO twice daily and leuprolide 22.5 mg every 12 weeks (Q12W) intramuscular (IM; A-APL arm) or abiraterone acetate 1000 mg PO QD plus prednisone 5 mg PO QD and leuprolide 22.5 mg IM Q12W (APL arm) for 24 weeks followed by RP.
• In part 2 of the study, the effect of an additional year of adjuvant therapy on 3-year biochemical PFS was evaluated. Patients were randomized (1:1) to receive either ERLEADA 240 mg PO QD in combination with abiraterone acetate 1000 mg PO QD plus prednisone 5 mg PO twice daily and leuprolide 22.5 mg Q12W IM for 12 months (Arm 2A) or observation (Arm 2B), stratified by neoadjuvant therapy and pathologic T stage.
• Select inclusion criteria: histologically confirmed adenocarcinoma of the prostate and candidates for RP based on urologic oncologic assessment; GS ≥4+3=7 or GS 3+4=7 with PSA >20 ng/mL or T3 disease; ≥3 biopsy cores positive for cancer, tumor size >1 cm on multiparametric magnetic resonance imaging (mpMRI), or T3 on mpMRI; and lymph nodes <20 mm as assessed by local radiologic review
• Select exclusion criteria: evidence of metastatic disease on radiologic imaging
• Primary endpoint: rate of pCR or MRD at RP (part 1); biochemical PFS at 3 years post-RP (part 2)
• Secondary endpoints: PSA response; pathologic staging; positive margins; intraoperative, perioperative, and postoperative AEs; mpMRI and tissue-based biomarkers associated with pathologic outcomes; and safety (part 1); freedom from further prostate cancer therapies (including systemic or radiation therapy), time to testosterone recovery (≥200 ng/dL), safety, and tolerability (part 2)

Results

Patient Characteristics

• Baseline characteristics were balanced between treatment arms.
• The median age of patients was 61 years (range, 46-72), and most patients (94%) had high-risk disease.
• The median PSA at study entry in the A-APL and APL arms was 7.1 ng/mL (range, 1.0-75) and 8.6 ng/mL (range, 2.1-78), respectively.
• Overall, 69% of patients enrolled in part 1 were randomized to part 2 of the study.

Efficacy

• Overall, 114 patients had pathologic assessment at RP.
• The centrally assessed pCR or MRD rate was similar between the treatment arms (1-sided 95% CI, 11%-14%; 1-sided P=0.4; Table: Part 1: Pathologic Outcomes at RP Based on Central Review).
• All patients with positive surgical margins had ypT3 disease (n=11/61 [18%]), and no patient with a positive margin or ypT3 disease had MRD.
• Most patients had significant residual tumor with ypT3 disease (A-APL, 49%; APL, 58%).
• The rates of lymph node involvement were numerically lower in the A-APL (7.3%) vs APL (17%) arm.
  • No patient with lymph node involvement had pCR/MRD.
• Pathologic responders at RP (pCR or MRD) vs nonresponders more likely had baseline <T3 stage (75% vs 29%), lower percent of positive biopsies (median 42% vs 73%), and lower maximum percent tumor involvement in biopsy (median 75% vs 90%).
• The median pre-RP PSA nadir was <0.01 ng/mL in the A-APL arm and 0.02 ng/mL in the APL arm, with the time to nadir of 4.2 months and 4.6 months, respectively.

• In part 2 of the study, the median follow-up was 50.2 months (range, 7.1-63.3) post-RP. In the intent-to-treat analysis, the 3-year biochemical PFS rate was 73% (90% CI, 57-84).
  • The 3‐year biochemical PFS rate was 83% versus 69%, respectively, for patients in the A-APL vs observation arm (HR, 0.50; 90% CI, 0.26-0.97).
  • Compared to nonresponders, patients who achieved pCR/MRD had improved 3-year biochemical PFS in the A-APL arm (79% vs 100%) as well as in the observation arm (63% vs 100%). However, compared to patients with <ypT3 disease, those with ≥ypT3 disease had worse 3-year biochemical PFS in the A-APL arm (94% vs 75%) as well as in the observation arm (89% vs 53%).
  • Of 36 patients in the A-APL arm, 80.6% had testosterone recovery and the median time to recovery from therapy end was 8.7 months (95% CI, 6.3-9.9). In the observation arm (n=42), 95.2% of patients had testosterone recovery and the median time to recovery from RP was 4.0 months (95% CI, 3.8-4.1).

Safety

• TRAEs were comparable in both arms, except for any-grade and grade 3 maculopapular rash, which was more common in the A-APL arm compared with the APL arm.
• A total of 13 (11%) patients experienced grade 3 TRAEs (A-APL, n=8; APL, n=5).
  • The most common grade 3 TRAE in the A-APL arm was hypertension (n=5) and in the APL arm was elevated ALT and AST (n=2, each).
• No grade 4 or 5 AEs were reported.
• Three patients discontinued treatment prior to RP due to toxicity in the A-APL arm. No AEs led to treatment discontinuation in the APL arm.
• In part 2 of the study, no new safety signals were observed.

Shore et al (2024)²¹ and Hafron et al (2021)²² reported results from the APA-RP study, a phase 2 study evaluating the efficacy and safety of the adjuvant treatment of ERLEADA and ADT in treatment-naïve patients with HRLPC who have undergone RP (N=108).

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 PO 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 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, 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; 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: 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
• Secondary endpoints: BCR-free rate at 12 months; serum testosterone recovery rate to ≥150 ng/dL at 18 and 24 months (6 and 12 months after the completion of adjuvant treatment with ERLEADA and ADT)
• Exploratory endpoints: incidence of skin rash; biomarker analysis; unconfirmed BCR (defined as patients with a PSA >0.2 ng/dL and no subsequent PSA value during the study)
• 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.

• Results from a substudy evaluating coadministration of ERLEADA and relugolix^25-28 and a subgroup analysis of Black and non-Black patients²⁹ have been reported.

Efficacy

• 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.
• The unconfirmed BCR-free rate at 24 months was 98.4% (90% CI, 92.2-99.7). 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.
• The serum testosterone recovery rate to ≥150 ng/dL following treatment completion was 34.9% (95% CI, 25.1-44.9) at 6 months post-treatment and 76.4% (95% CI, 65.084.5) at 12 months post-treatment. Serum testosterone recovery rate to ≥50 ng/dL at 6 and 12 months post-treatment were 62.6% (95% CI, 51.3-72.0) and 95.2% (95% CI, 86.9-98.3), respectively.

Safety

• TEAE safety data is reported in Table: APA-RP Study Safety Data.

• Use of a pre-specified 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 and compared descriptively with the North American safety populations for rash from the global SPARTAN (n=283) and TITAN (n=63) studies.²⁴
  • Any-grade and grade 3 rash were reported in 21.3% and 13.0% of patients in the APA-RP study, 28.3% and 22.5% of patients in the SPARTAN study, and 33.3% and 33.3% of patients in the TITAN study, with 95.7%, 93.8%, and 57.1% experiencing resolution of rash, respectively. Treatment reductions, interruptions, and discontinuations were reported in 4.3%, 26.0%, and 0% of patients in the APA-RP study, 10.0%, 23.8%, and 6.3% of patients in the SPARTAN study, and 19.0%, 33.3%, and 9.5% of patients in the TITAN study, respectively.

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 21 May 2024.