SUMMARY

• In the phase 3 TITAN study which evaluated ERLEADA compared to placebo in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving continuous androgen deprivation therapy (ADT), patients were excluded if radiation therapy (RT) was administered within 28 days of randomization. Additionally, concomitant RT for new painful metastatic prostate cancer lesions that were not present on baseline imaging was prohibited. Efficacy and safety analyses were not performed for patients who received palliative radiation to lesions at baseline in the TITAN study.^1,2
• In the phase 3 SPARTAN study which evaluated the efficacy and safety of ERLEADA compared to placebo in patients with high-risk, non-metastatic castration-resistant prostate cancer (nmCRPC) receiving continuous ADT, patients were permitted to receive salvage radiation for loco-regional pelvic disease to treat localized progression or symptoms while continuing treatment with ERLEADA.^3,4 Two patients (0.2%) and 1 patient (0.3%) in the ERLEADA and placebo groups, respectively, received concomitant RT. Efficacy and safety analyses were not performed for patients who received concomitant RT in the SPARTAN study.⁵
• ATLAS (NCT02531516) is an ongoing, phase 3, randomized, double-blind, placebo-controlled, 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 ongoing. Efficacy and safety results have not been published.^6-8
  • 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.⁸
  • Patient retention and physician engagement strategies were initiated during the coronavirus disease 2019 (COVID-19) pandemic, and a 96% patient retention rate was observed.⁹
• PRIMORDIUM (NCT04557059) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of adding ERLEADA to RT and a luteinizing hormone-releasing hormone agonist (LHRHa) compared to RT and a LHRHa alone in patients with high-risk, prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-positive hormone-sensitive prostate cancer (HSPC). The primary endpoint is PSMA-PET metastatic progression-free survival (ppMPFS). This study also includes an observational cohort of PSMA-PET-negative patients. Efficacy and safety results have not been published. Baseline characteristics of patients enrolled in both cohorts through the data cutoff date January 12, 2023 have been published.^10-12
• STARTAR (NCT03311555) is a phase 2 study which evaluated salvage treatment in patients with prostate-specific antigen (PSA) recurrent prostate cancer after radical prostatectomy (RP; N=39). Patients were treated with ERLEADA and ADT plus salvage RT followed by docetaxel. At primary analysis, with a median follow-up of 36 months, all patients achieved undetectable PSA nadirs. The PFS rate was 84% and 72% at 24 months and 36 months, respectively, with 95% of patients recovering testosterone at 36 months. Common any-grade adverse events (AEs) included hot flashes (98%), fatigue (88%), alopecia (77%), dysgeusia (57%), rash (53%), and febrile neutropenia (5%).^13,14
• FORMULA-509 (NCT03141671) is an ongoing, phase 2, randomized, open-label, multicenter study designed to evaluate the efficacy and safety outcomes of adding 6 months of ERLEADA and abiraterone acetate plus prednisone (AAP) to the standard-of-care (SOC) of 6 months of GnRHa with salvage RT in patients with unfavorable features and a detectable PSA post-RP (N=345). Patients received salvage RT plus 6 months of GnRHa and were randomized to concurrent ERLEADA 240 mg once daily (QD) plus abiraterone acetate 1000 mg plus prednisone 5 mg or bicalutamide 50 mg. In the ERLEADA plus AAP group vs bicalutamide group, the 3-year progression-free survival (PFS) was 74.9% vs 68.5% (HR, 0.71; 90% CI, 0.49-1.03). For baseline PSA >0.5 (HR, 0.50; 90% CI, 0.30-0.86), the 3-year PFS was 67.2% vs 46.8%.¹⁵
• SATURN (NCT03902951), a prospective, phase 2, single-arm, single-center study, evaluated the efficacy and safety of adding ERLEADA, AAP, and PSMA-PET/computed tomography (CT)-guided metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT for patients with oligorecurrent metastatic HSPC after prior RP (N=28). The primary endpoint was the percentage of patients with PSA <0.05 ng/mL 6 months after serum testosterone recovery to ≥150 ng/dL following androgen annihilation therapy (AAT).¹⁶
  • At 6 months after testosterone recovery, PSA was maintained at <0.05 ng/mL in 13 of 26 (50%) evaluable patients (95% CI, 32-67).
  • The rates of grade 2 and 3 AAT toxicity were 21% each.
• SOLAR (NCT03298087), a prospective, phase 2, single-arm study, evaluated the efficacy and safety of combining radical local (RP with lymph node dissection and postoperative RT or radical RT directed to the prostate, seminal vesicles, and pelvic lymph nodes) metastasis-directed stereotactic ablative RT (SBRT), and intensified systemic therapies of limited duration (6 months on leuprolide, AAP, and ERLEADA) in veterans with de novo oligometastatic prostate cancer (N=28). The primary endpoint was the percentage of patients with undetectable serum PSA (for RP) or PSA <2 ng/mL (for radical RT) 6 months after testosterone recovery to ≥150 ng/dL.¹⁷
  • At a median follow-up of 30 months among 22 evaluable patients, 19 (86%) patients were progression-free.
  • Grade 2 and 3 toxicities, respectively, were reported in 46% and 4% of patients on primary tumor therapy; no patients on SBRT; and 42% and 4% of patients on systemic therapy. There was one grade 4 toxicity event.
• Interim results from an ongoing phase 2 study in patients treated with ERLEADA plus AAP plus leuprolide and ultra-hypofractionated radiation (UHRT) have been reported (N=64). The 3-year biochemical recurrence-free survival (bRFS) was 89.7%. Grade 3 toxicities were reported in 15 patients (hypertension [n=12] and rash [n=3]).^18,19
• Additionally, the study descriptions of ongoing phase 3 studies^20,21 and ongoing phase 2 studies^22-25 in patients treated with ERLEADA and concurrent RT have been published.
• Results from a real-world study evaluating the impact of prostate RT in patients with mHSPC receiving ERLEADA have been published (N=266).²⁶

Clinical Data

Phase 3 Studies

TITAN Study

Chi et al (2019)¹ evaluated the efficacy and safety of ERLEADA plus ADT compared to placebo plus ADT in patients with mCSPC (N=1052). Patients were randomized 1:1 to receive either ERLEADA 240 mg orally (PO) QD (n=525) or placebo QD (n=527). All patients in the TITAN study received a concomitant GnRH analog or had a bilateral orchiectomy (NCT02489318).

Patients were excluded if RT was administered within 28 days of randomization. Concomitant RT for new painful metastatic prostate cancer lesions that were not present on baseline imaging was prohibited. Additionally, patients discontinued ERLEADA treatment due to clinical progression, which included the need to initiate RT due to tumor progression (even in the absence of radiograph evidence of disease). Palliative radiation to lesions existing at baseline was not considered clinical progression.²

Efficacy and safety analyses were not performed for patients who received palliative radiation to lesions at baseline in the TITAN study.

SPARTAN Study

Smith et al (2018)³ study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC (N=1207). Patients were randomized 2:1 to receive either
ERLEADA 240 mg PO QD (n=806) or placebo QD (n=401). All patients in the SPARTAN study received a concomitant GnRH analog or had a bilateral orchiectomy. Salvage radiation for loco-regional pelvic disease to treat localized progression or symptoms was permitted while continuing treatment with ERLEADA (NCT01946204).⁴

Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median treatment duration was
16.9 months in the ERLEADA group and 11.2 months in the placebo group.^3,5 Shown below is Table: Frequency of Concomitant Radiotherapy in the SPARTAN Study.

Efficacy and safety analyses were not performed for patients who received concomitant RT in the SPARTAN study.

Additional Information

Additional information regarding the SPARTAN study, including the clinical study report, protocol, and statistical analysis plan, can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm (scroll to the “Sponsor Clinical Study Reports ARN-509-003 SPARTAN NCT # 01946204” section at the bottom of the web page).

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.^6-8

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multicenter study
• A total of 1503 patients were randomized 1:1 to receive the following treatments during each 28-day treatment cycle:
  • Cycles 1-2 (neoadjuvant to RT)
    • Group 1: ERLEADA 240 mg QD, bicalutamide placebo, and GnRHa
    • Group 2: Placebo, bicalutamide, and GnRHa
  • Cycles 3-4 (concurrent with RT)
    • Group 1: RT with ERLEADA 240 mg QD, bicalutamide placebo, and GnRHa
    • Group 2: RT with placebo, bicalutamide, and GnRHa
  • Cycles 5-30 (adjuvant to RT)
    • Group 1: ERLEADA 240 mg QD and GnRHa
    • Group 2: Placebo and GnRHa
• Patients were stratified by Gleason score (GS), pelvic nodal status, use of brachytherapy boost, and region.
• 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 RT and hormonal therapy.
• Select inclusion criteria: Indicated and planned to receive primary RT for prostate cancer; histologically confirmed adenocarcinoma of an intact prostate and either GS ≥8 and ≥clinical stage T2c (≥cT2c) or GS ≥7, PSA ≥20 ng/mL and ≥cT2c; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; Charlson Comorbidity Index (CCI) ≤3; and adequate liver function
• Select exclusion criteria: Presence of distant metastasis and history of pelvic radiation; prior treatment with GnRH analog, antiandrogen, or both for >3 months prior to randomization; prior procedural or systemic treatment for prostate cancer; cytochrome P450 17 (CYP17) inhibitors, radiopharmaceutical agents, immunotherapy, or any investigational agent; prior treatment with systemic glucocorticoids ≤4 weeks prior to randomization or is expected to require long-term use of corticosteroids during the study; and history of seizure
• Primary endpoint: MFS
• Key secondary endpoints: Event-free survival (EFS), time to PSA progression, and overall survival (OS)
• Other secondary endpoints: Time to next local or systemic treatment, time to distant metastasis, and MFS by conventional or PET imaging
• 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.⁹

Efficacy and safety results of the ATLAS study have not been published.

PRIMORDIUM Study

PRIMORDIUM is an ongoing, phase 3, randomized, open-label, multicenter, global study evaluating the efficacy and safety of adding ERLEADA to RT and a LHRHa compared to RT and a LHRHa alone in high-risk patients with PSMA-PET-positive HSPC. Patients who are PSMA-PET-negative at baseline will be enrolled into the observational cohort.^10,12

Study Design/Methods

• A total of ~412 PSMA-PET-positive patients to achieve ~192 events and ~200 PSMA-PET-negative patients will be included in the interventional and observational cohorts, respectively. This study is not designed to compare results across cohorts.
• The treatments in the interventional cohort are randomized 1:1 as described in the Table: Treatments in the Interventional Cohort.
• Patients who are PSMA-PET-negative and enrolled in the observational cohort will receive SOC treatment per local practice and will have data collected during routine clinical practice which will include therapies administered, clinical evaluations, disease progression assessments, and survival until closure of the interventional cohort.

Treatments in the Interventional Cohort^10,12,a

• Patients in the interventional cohort will be stratified by location of PSMA-PET-positive lesions, PSA doubling-time (PSADT), and planned use of SBRT.
  • At sites where it is a standard approach, SBRT may be used for ≤3 PSMA-avid distant metastases; the decision to use SBRT must be made before randomization.
• In the interventional cohort, PSA will be measured every 3 months until the primary endpoint. If the PSA remains <0.2 ng/mL, PSMA-PET is assessed by BICR at 6 and 12 months, then annually until PSMA-PET progression. If PSA rises to ≥0.2 ng/mL, PSMA-PET is done immediately then every 6 months until PSMA-PET progression. Testosterone and patient-reported outcomes (PROs) will additionally be assessed.
  • Post-PSMA-PET-progression assessments will include bone scans, CT/magnetic resonance imaging (MRI), and PROs.
• Select inclusion criteria: histologically confirmed adenocarcinoma of the prostate; previously treated with RP with or without lymph node dissection and either any post-operative PSA of <0.1 ng/mL within 12 months after RP and without any PSA ≥0.1 ng/mL within the 4- to 8-week period after RP for biochemical recurrence after RP or PSA ≥0.1 ng/mL within the 4- to 8-week period after RP for persistent PSA after RP, confirmed by additional measurement ≥3 weeks later; biochemically recurrent prostate cancer after RP with high risk of developing metastasis defined as pathological GS ≥8 or PSADT ≤12 months; no evidence of metastases on screening CT/MRI of the chest/abdomen/pelvis, and technetium-99m (^99mTc) whole-body bone scan; ECOG PS 0 or 1; results of PSMA-PET at screening as determined by BICR had to be:
  • PSMA-PET-negative for any prostate cancer lesions (ie, no locoregional lesion and no distant lesions)
  • PSMA-PET-positive for ≥1 locoregional (pelvic) lesion without distant extra pelvic lesion
  • PSMA-PET-positive for ≥1 loco-regional (pelvic) lesion with extra pelvic lesion(s)
• Select exclusion criteria: history of pelvic radiation for malignancy; history of ADT or chemotherapy for prostate cancer; prior treatment for biochemical recurrence; prior treatment with a CYP17 inhibitor, androgen receptor (AR) antagonist, medication that lowers androgen levels, or bilateral orchiectomy; small cell or neuroendocrine carcinoma of the prostate; clinically significant cardiovascular disease; use of 5-alpha-reductase inhibitor or an investigational agent ≤4 weeks prior to randomization; history of seizure or at increased risk of seizure  
• Primary endpoint: ppMPFS, defined as the appearance of at least 1 new PSMA-PET-positive distant lesion compared with the previous scan assessed by BICR, or death
• Secondary endpoints: time to PSA progression; PSA response rate; PSA levels at end of week 26; time to locoregional progression by PSMA-PET; overall survival (OS); prostate cancer-specific survival; and AEs

Results

• Efficacy and safety results have not been published.

Phase 2 Studies

STARTAR Study

Zhang et al (2023)¹³ reported primary analysis results from a phase 2 study evaluating salvage treatment in patients with PSA recurrent prostate cancer after RP treated with ERLEADA and ADT plus RT followed by docetaxel (N=39).

Study Design/Methods

• Phase 2, open label, single arm, multicenter study¹⁴
• Patients were treated with ERLEADA and ADT for approximately 9 months plus
  • RT of 66-74 Gy to the prostate bed ± pelvic lymph nodes over 68 weeks starting week 8, followed by docetaxel 75 mg/m² IV every 3 weeks for 6 cycles.
• Select inclusion criteria: GS 7 with T3/positive margin/N1 or GS 8-10 prostate cancer, PSA relapse <4 years post-RP (inclusion PSA 0.2-4 ng/mL), and <4 positive lymph nodes, standard imaging negative
• Select exclusion criteria: radiographic evidence of metastatic disease, PSA ≥4.0 ng/mL, and testosterone level of ≤100 ng/dL¹⁴
• Primary endpoint: PFS at 36 months
• Secondary endpoints: 1-year PSA recurrence; testosterone recovery defined as testosterone levels >100 ng/dL; safety assessments¹⁴

Results

Patient Characteristics

• The median follow-up from enrollment was 36 months.
• A total of 54% and 46% of patients had a GS of 7 and 8-10, respectively.
• Positive lymph nodes were reported in 23% of patients.
• The median baseline PSA was 0.58 ng/mL (range, 0.21-3.40).
• The median time from RP was 7.6 months (range 2-98 months).
• There were 37 (95%) patients and 23 (62%) patients who completed ≥1 and all 6 cycles of docetaxel, respectively.

Efficacy

• All patients achieved undetectable PSA nadirs.
• The PFS rate was 84% and 72% at 24 months and 36 months, respectively.
• Testosterone recovery was observed in 95% of patients at 36 months.

Safety

• Common any-grade AEs included hot flashes (98%), fatigue (88%), alopecia (77%), dysgeusia (57%), rash (53%), and febrile neutropenia (5%).
  • Of the rash AEs, 28% were grade 1, 15% were grade 2, and 10% were grade 3.

FORMULA-509 Study

Nguyen et al (2023)¹⁵ evaluated the efficacy and safety outcomes of adding 6 months of ERLEADA and AAP to the SOC of 6 months of GnRHa with salvage RT in patients with unfavorable features and a detectable PSA post-RP (N=345).

Study Design/Methods

• Phase 2, randomized, open-label, multicenter study
• Patients received salvage RT plus 6 months of GnRHa and randomization was to concurrent ERLEADA 240 mg QD plus abiraterone acetate 1000 mg plus prednisone 5 mg or bicalutamide 50 mg. Radiation to pelvic nodes was required for pN1 and optional for pN0.
• Patients were stratified by PSA at study entry (>0.5 vs ≤0.5) and pN0 vs pN1.
• Select inclusion criteria: PSA ≥0.1 post-RP and ≥1 unfavorable features: Gleason 8-10, PSA >0.5, pT3/T4, pN1 or radiographic N1, PSADT <10 months, negative margins, persistent PSA, gross local/regional disease, or high risk on Decipher test).
• Primary endpoint: PSA PFS
• Secondary endpoint: MFS, determined by conventional imaging

Results

Patient Characteristics

• Twenty-nine percent of patients were pN1 and 31% of patients had PSA>0.5 ng/mL.

Efficacy

• Results are summarized in Table: Primary and Secondary Endpoint Results.
• The median follow-up was 34 months.
• In a pre-planned analysis by stratification factors, the ERLEADA plus AAP group was superior to the bicalutamide group for PSA >0.5 for PFS (HR, 0.50; 90% CI, 0.30-0.86; 2-sided P-value=0.03 and 3 year PFS 67.2% vs 46.8%) and MFS (HR, 0.32; 90% CI, 0.15-0.72; 2-sided P-value=0.01 and 3 year MFS 84.3% vs 66.1%).

HRQoL Outcomes

• Patient-reported HRQoL was also evaluated using validated questionnaires at baseline, end of treatment, and 1 year after treatment. Both treatment arms demonstrated clinically meaningful declines in EPIC-26 hormonal domain (median change, -15 bicalutamide group, -15 ERLEADA plus AAP group) and increases in PROMIS Fatigue (median change, 6 bicalutamide group, 7.4 ERLEADA plus AAP group) from baseline to end of treatment, which improved to near baseline at 1 year after treatment for both groups. Median Saint Louis University Mental Status Exam (SLUMS) score was within normal range at baseline, end of treatment, and 1 year after treatment for both groups. There was no significant difference in patient-reported hormonal function, fatigue, or mental status between groups at end of treatment and 1 year after treatment.²⁷

Safety

• AEs were consistent with the known safety profiles of each medication, with more rash and hypertension reported in the ERLEADA plus AAP group (incidence not reported).

McBride et al (2021)¹⁹ reported interim results of an ongoing phase 2 study in very high-risk patients with node negative prostate cancer treated with ERLEADA plus AAP plus leuprolide in conjunction with UHRT (N=64).¹⁸

Study Design/Methods

• Phase 2, open-label, single arm study
• Patients received treatment for 6 months with ERLEADA in combination with¹⁹:
  • AAP plus
  • Leuprolide and UHRT 7.5-8 Gy x 5 fractions
• Select inclusion criteria: very high-risk prostate cancer defined as having a GS of 9-10, or >4 cores of GS 8 disease, or 2 high-risk features (including rT3/T4 disease)
• Select exclusion criteria: radiographic evidence of metastatic disease, ≥1 positive lymph node as determined by radiographic assessment of MRI or CT, severe hepatic impairment (Child-Pugh Class C), and prior treatment for prostate cancer except for patient who received LHRH agonist/antagonist therapy for ≤1 month prior to study enrollment¹⁸
• Primary endpoint: biochemical recurrence (BCR) defined as nadir PSA + 2 ng/mL¹⁹

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 45 patients had a GS of 9-10, 14 patients had a GS of 8, and 5 patients 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 level 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).

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 04 June 2024.