SUMMARY  

• PRESTO (AFT-19; NCT03009981) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of ERLEADA plus androgen deprivation therapy (ADT), ERLEADA plus abiraterone acetate plus prednisone (AAP) plus ADT, and ADT in patients with high-risk biochemically relapsed prostate cancer (BRPC) following prior radical prostatectomy (RP) without metastases on conventional imaging and a prostate-specific antigen (PSA) doubling time (PSADT) of ≤9 months (N=503). The primary endpoint was PSA progression-free survival (PSA-PFS).^1,2
  • In the first interim analysis at a median follow-up of 21.5 months, PSA-PFS was significantly prolonged for the ERLEADA + ADT arm vs the ADT arm (median, 24.9 months vs 20.3 months; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.35-0.77; P=0.00047). PSA-PFS was also significantly longer at a median follow-up of 21.3 months for the ERLEADA + AAP + ADT arm vs the ADT arm (median, 26.0 months vs 20.0 months; HR, 0.48; 95% CI, 0.32-0.71; P=0.00008).
  • In an updated analysis at a median time from randomization to last contact of 26.5 months (ERLEADA + ADT vs ADT) and 26.8 months (ERLEADA + AAP + ADT vs ADT), the ERLEADA + ADT arm (HR, 0.59; 97.5% CI, 0.40-0.85; 1-sided P=0.0006) and the ERLEADA + AAP + ADT arm (HR, 0.53; 97.5% CI, 0.36-0.77; 1-sided P=0.00006) prolonged biochemical progression-free survival (bPFS) compared with the ADT arm.³
  • Any-grade treatment-emergent adverse events (TEAEs) were reported in 145 (91%), 148 (91%), and 155 (96%) patients treated with ADT, ERLEADA + ADT, and ERLEADA + AAP + ADT, respectively. There were no treatment-related deaths. The most frequently reported grade ≥3 adverse event (AE) was hypertension in all arms (Table: Most Common TEAEs of Clinical Interest).¹
• PRIMORDIUM (NCT04557059) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of adding ERLEADA to radiotherapy and a luteinizing hormone-releasing hormone agonist (LHRHa) compared to radiotherapy and 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.^4-6
• INDICATE (NCT04423211) is an ongoing, phase 3, randomized, open-label study evaluating the use of ERLEADA in patients with prostate cancer with post-prostatectomy biochemical recurrence. Patients in cohort 1 (PET-negative) will be randomized to standard of care (SOC) salvage therapy (ST) with or without ERLEADA for 6 months, and patients in cohort 2 (PET-positive for extra-pelvic metastases) will be randomized to SOC ST and ERLEADA with or without metastasis-directed radiation therapy (RT) to PET-positive lesions. The primary endpoint is PFS and primary objectives are to evaluate whether addition of ERLEADA to SOC ST and addition of metastasis-directed RT to SOC ST and ERLEADA could prolong PFS in cohorts 1 and 2, respectively. Efficacy and safety results have not been published.^7,8
• STARTAR (NCT03311555) is a phase 2 study which evaluated salvage treatment in patients with PSA recurrent prostate cancer after 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 AEs included hot flashes (98%), fatigue (88%), alopecia (77%), dysgeusia (57%), rash (53%), and febrile neutropenia (5%).^9,10
• FORMULA-509 (NCT03141671) is an ongoing, phase 2, randomized, open-label, multicenter study evaluating the efficacy and safety outcomes of adding 6 months of ERLEADA and AAP to the SOC of 6 months of gonadotropin hormone-releasing hormone agonist (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 randomization was 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 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%.¹¹
• ARN-509-002 is a phase 2, randomized, open-label, multicenter study designed to evaluate the efficacy, health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy-Prostate (FACT-P), and safety of ERLEADA, ADT, and ERLEADA plus ADT in patients with BRPC (N=90). At 12 months, there was no significant difference in HRQoL based on least squares (LS) mean change from baseline in FACT-P scores between the ERLEADA monotherapy and ADT monotherapy groups (LS mean change, 1.45; 2-sided 97.5% CI, -6.23 to 9.12; P=0.669), or between the ERLEADA plus ADT and ADT monotherapy groups (LS mean change, -1.38; 2-sided 97.5% CI, -8.72 to 5.97). Grade ≥3 AEs were reported in 17.2%, 13.8%, and 29.0% of patients in the ERLEADA, ADT, and ERLEADA plus ADT groups, respectively.¹²
• Study description of an ongoing phase 2 study and results from an additional phase 2 study that included patients with multiple clinical states of prostate cancer have been published, however, results were not delineated for patients with BRPC.^13-15

Guidelines

• In the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Prostate Cancer, the following treatment options are noted in PROS-12:¹⁶
  • In the treatment for progressive M0 castration-sensitive prostate cancer (CSPC) after maximal pelvic therapy, apalutamide plus ADT is an option useful in certain circumstances: patients with biochemical recurrence after RP who meet the following high-risk criteria: PSADT <9 months; PSA >0.5 ng/mL; and prior adjuvant or secondary radiation therapy (RT) or not considered a candidate for RT (category 2B).^*
• Please refer to the NCCN Guidelines^® for Prostate Cancer at www.nccn.org for current and complete recommendations for the use of apalutamide in prostate cancer.¹⁶ 
• Please refer to the full Prescribing Information for ERLEADA (apalutamide) for information on INDICATIONS AND USAGE.¹⁷ 
• ^*Aggarwal R, et al. J Clin Oncol 2024;42:1114-1123.

CLINICAL DATA

Phase 3 Studies

PRESTO Study

PRESTO (AFT-19) is an ongoing study evaluating the efficacy and safety of ERLEADA plus ADT, ERLEADA plus AAP plus ADT, and ADT alone in patients with high-risk BRPC following prior RP without metastases on conventional imaging and a PSADT of ≤9 months (N=503).²

Study Design/Methods

• Phase 3, randomized, open-label, multicenter study
• Patients were randomized 1:1:1 to receive the following treatments:
  • ADT arm: LHRH analog (degarelix or other drug per investigator discretion; n=166)
  • ERLEADA + ADT arm: ERLEADA 240 mg orally (PO) QD + ADT as above (n=168)
  • ERLEADA + AAP + ADT arm: ERLEADA 240 mg PO QD + abiraterone acetate 1000 mg PO QD + prednisone 5 mg PO QD + ADT as above (n=169)
• The planned duration of treatment was 52 weeks in the absence of PSA or radiographic progression, unacceptable toxicity, or study withdrawal.
• During the treatment period, serum PSA and AE assessment were performed every 28 days and during the follow-up observation phase, serum PSA and total testosterone levels were assessed monthly. Patients with PSA progression were followed long term with treatment administered per the investigator’s discretion.
• Patient randomization was stratified by baseline PSADT (<3 months vs 3-9 months).
• Select inclusion criteria: histologically confirmed prostate adenocarcinoma; prior RP; BRPC with PSADT ≤9 months at the time of study entry; screening PSA >0.5 ng/mL; no evidence of metastases on conventional imaging; screening serum testosterone >150 ng/dL²
• Select exclusion criteria: prior ADT and/or first generation antiandrogen (eg, bicalutamide, nilutamide, flutamide) for BRPC (prior ADT and/or first generation antiandrogen in the [neo]adjuvant and/or salvage setting before, during, and/or following radiation or surgery allowed provided last effective dose of ADT and/or first generation antiandrogen is >9 months prior to date of randomization and total duration of prior therapy is ≤36 months)²
• Primary endpoint: PSA-PFS, defined as time from the date of randomization to PSA progression or death. During the treatment period, PSA progression was defined as a rise of ≥25% and 2 ng/mL above nadir, confirmed by repeat measurement. During follow-up, PSA progression was defined as the first date by which PSA levels >0.2 ng/mL were recorded, confirmed on repeat measurement ≥2 weeks later.
• Select secondary endpoints: PSA-PFS in the testosterone-recovered population (defined as the subset of patients who recovered serum testosterone to >50 ng/dL during follow-up), median time to testosterone recovery (TTTR) to >50 ng/dL, and safety

Results

Baseline Characteristics

• Select baseline characteristics of patients are reported in Table: Select Baseline Characteristics.

Efficacy

• There were 383 (76%) patients that completed the 52-week treatment period, and 63 (13%) patients remain on study treatment.
  • Reasons for discontinuation included: withdrawal in 27 (5%) patients, PSA progression in 10 (2%) patients, AE in 8 (2%) patients, and other reasons in 12 (2%) patients.
• At the first interim analysis:
  • In the ERLEADA + ADT arm, PSA-PFS was significantly prolonged compared with the ADT arm (median, 24.9 months vs 20.3 months; HR, 0.52; 95% CI, 0.35-0.77; P=0.00047) after a median follow-up of 21.5 months and 102 PSA-PFS events.
  • In the ERLEADA + AAP + ADT arm, PSA-PFS was significantly prolonged compared with the ADT arm (median, 26.0 months vs 20.0 months; HR, 0.48; 95% CI, 0.32-0.71; P=0.00008) after a median follow-up of 21.3 months.
  • In the analysis of ERLEADA + ADT vs ADT, 152 patients recovered serum testosterone to >50 ng/dL after treatment completion. In this subgroup, the addition of ERLEADA to ADT significantly prolonged PSA-PFS compared with ADT alone (HR, 0.53; 95% CI, 0.34-0.82).
  • In the analysis of ERLEADA + AAP + ADT vs ADT, 149 patients recovered serum testosterone to >50 ng/dL after treatment completion. In this subgroup, the addition of ERLEADA + AAP to ADT prolonged PSA-PFS compared with ADT alone (HR, 0.60; 95% CI, 0.39-0.92).
• In an updated analysis³:
  • The median time from randomization to last contact for the analyses of ERLEADA + ADT vs ADT and ERLEADA + AAP + ADT vs ADT was 26.5 months and 26.8 months, respectively.
  • There were 146 bPFS events in the ADT arm vs ERLEADA + ADT arm and 142 events in the ADT arm vs ERLEADA + AAP + ADT arm.
  • In the ERLEADA + ADT arm, bPFS was significantly prolonged compared with the ADT arm (HR, 0.59; 97.5% CI, 0.40-0.85; 1-sided P=0.0006).
  • In the ERLEADA + AAP + ADT arm, bPFS was significantly prolonged compared with the ADT arm (HR, 0.53; 97.5% CI, 0.36-0.77; 1-sided P=0.00006).
  • The median TTTR for the ADT, ERLEADA + ADT, and ERLEADA + AAP + ADT arms was 3.9, 3.8, and 4.7 months, respectively.
• There was no significant difference in TTTR after treatment completion, accounting for competing risks of death or metastatic disease, in the ERLEADA + ADT or ERLEADA + AAP + ADT arms compared with the ADT arm.

HRQoL Outcomes

• Mean changes in HRQoL from baseline to end of treatment in each treatment arm were assessed using the Hot Flash Related Daily Interference Scale (HFRDIS), Expanded Prostate Cancer Index Composite (EPIC)-26 Sexual domain, Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form, and EQ-5D-5L. Between-arm mean differences in HRQoL were estimated using general linear mixed modeling in an intent-to-treat approach. For each measure, the mean differences between the ADT arm and the ERLEADA + ADT or ERLEADA + AAP + ADT arms were not statistically significant. Additionally, the numerical differences between treatment arms for each HRQoL measure did not meet published minimally clinically important difference thresholds.¹⁸

Safety

• A summary of TEAEs at the first interim analysis is described in Table: Most Common TEAEs of Clinical Interest. There were no treatment-related deaths.

• In an updated analysis³:
  • Hypertension was the most common grade ≥2 AE in the ADT (19%), ERLEADA + ADT (23%), and ERLEADA + AAP + ADT (30%) arms.
  • Treatment discontinuations occurred in 3 (2.1%) and 5 (3.4%) patients in the ERLEADA + ADT and ERLEADA + AAP + ADT arms, respectively.

PRIMORDIUM Study

PRIMORDIUM is an ongoing, phase 3, randomized, open-label, multicenter, global study evaluating the efficacy and safety of adding ERLEADA to radiotherapy and a LHRHa compared to radiotherapy 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.^4-6

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.

• Patients in the interventional cohort will be stratified by location of PSMA-PET-positive lesions, PSADT, and planned use of stereotactic body radiotherapy (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 blinded independent central review (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, computed tomography (CT)/magnetic resonance imaging (MRIs), and PROs.
• Select inclusion criteria: histologically confirmed prostate adenocarcinoma; prior RP with postoperative PSA <0.1 ng/mL; biochemically recurrent prostate cancer after RP with Gleason score ≥8 or PSADT ≤12 months; no evidence of metastases in chest/abdomen/pelvis CT/MRI and technetium-99m (^99mTc) whole-body bone scan; Eastern Cooperative Oncology Group performance status (ECOG PS) grade 0 or 1
  • PSMA-PET at screening for interventional cohort: patients who are PSMA-PET-positive for ≥1 locoregional (pelvic) lesion with or without distant (extra pelvic) lesions at screening, as determined by BICR
  • PSMA-PET at screening for observational cohort: patients who are PSMA-PET-negative for any prostate cancer lesions (ie, no loco regional lesion and no distant lesions) at screening, as determined by BICR
• 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

Baseline Characteristics

• Baseline characteristics of patients enrolled in both cohorts through the data cutoff date January 12, 2023 are reported in Table: Baseline Characteristics of Interventional and Observational Cohorts.
• By the data cutoff date, enrolled patients were from Australia, Austria, Belgium, Brazil, Czech Republic, Denmark, Hungary, Italy, Lebanon, Poland, Portugal, Russian Federation, Slovakia, Spain, Sweden, and Turkey in both cohorts, with the exception of Hungary (observational cohort only) and Lebanon (interventional cohort only). As of December 31, 2023, the United States is among the countries added with active sites.

• Efficacy and safety results have not been published.

Phase 2 Studies

STARTAR Study

Zhang et al (2023)⁹ 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 study¹⁰
• 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: Gleason score 7 with T3/positive margin/N1 or Gleason score 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/dL¹⁰
• Primary endpoint: PFS at 36 months
• Secondary endpoints: 1-year PSA recurrence; testosterone recovery defined as testosterone levels >100 ng/dL; safety assessments¹⁰

Results

Patient Characteristics

• The median follow-up from enrollment was 36 months.
• A total of 54% and 46% of patients had a Gleason score 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)¹¹ 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^®
• Primary endpoint: PSA-PFS
• Secondary endpoint: Metastasis-free survival (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.¹⁹

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).

ARN-509-002 Study

Aggarwal et al (2022)¹² evaluated the efficacy, HRQoL per FACT-P, and safety of ERLEADA, ADT, and ERLEADA plus ADT in patients with BRPC after primary definitive local therapy and PSADT ≤12 months (N=90).

Study Design/Methods

• Phase 2, randomized, open-label, multicenter study
• Patients were randomized 1:1:1 to receive ERLEADA 240 mg daily, ADT, or ERLEADA plus ADT for 12 months, followed by a 12-month observation period off therapy.
• Patients were stratified by PSADT (<6 vs 6-12 months) and age (≤70 vs >70 years).
• Select inclusion criteria: patients aged ≥18 years with BRPC and PSADT ≤12 months after RP and/or RT undertaken with curative intent; no evidence of metastatic disease on CT or MRI of the abdomen/pelvis and whole-body nuclear bone scan; prior primary or salvage radiation or not a candidate for localized salvage radiation; minimum PSA of 1.0 ng/mL in patients who received prior RP with or without adjuvant or salvage radiation or PSA nadir plus 2.0 ng/mL in patients who had definitive RT without prior RP; serum testosterone level ≥150 ng/dL; ECOG PS of 0 or 1
• Select exclusion criteria: treatment with an oral antiandrogen ≤6 weeks prior to randomization; prior treatment with ADT for BRPC; treatment with 5alpha reductase antagonist ≤6 weeks prior to randomization; prior bilateral orchiectomy
• Primary endpoint: mean change in FACT-P total score from baseline to 12 months
• Key secondary endpoints: PSA <0.2 ng/mL at 7 months, time to PSA progression, TTTR, bone mineral density, HRQoL over time, and safety
• Exploratory biomarker analyses were performed using AR, DECIPHER^®, and PAM50 molecular classifiers and archival tumor tissue samples, as well as a custom 36-gene biomarker panel and blood samples.

Results

Patient Characteristics

• Baseline demographic and disease characteristics were similar between the 3 groups (Table: Select Patient Baseline Characteristics [ITT Population]).

Efficacy

• A total of 89.7%, 86.7%, and 93.5% of patients in the ERLEADA, ADT, and ERLEADA plus ADT groups completed 12 months of protocol-defined treatment.
• At 12 months, there was no significant difference in HRQoL based on LS mean change from baseline in FACT-P scores between the ERLEADA monotherapy and ADT monotherapy groups (LS mean change, 1.45; two-sided 97.5% CI, -6.23 to 9.12; P=0.669), or between the ERLEADA plus ADT and ADT monotherapy groups (LS mean change, -1.38; two-sided 97.5% CI, -8.72 to 5.97).
  • As the lower limit of 97.5% CI crossed the noninferiority margin of -7, the noninferiority of the ERLEADA plus ADT group vs ADT monotherapy group was not demonstrated.
• A total of 96.6% of patients treated with ERLEADA plus ADT achieved PSA nadir <0.2 ng/mL at 7 months compared with 88.9% treated with ERLEADA alone and 88.5% treated with ADT alone.
• After discontinuation of therapy, PSA progression in the ERLEADA, ADT, and ERLEADA plus ADT groups was observed in 48.3%, 40.0%, and 38.7% of patients, respectively; however, the differences were not statistically significant.
• Median time to PSA progression was 25.8, 30.9, and 36.1 months in the ERLEADA, ADT, and ERLEADA plus ADT groups, respectively.
  • Compared with ADT alone, treatment with ERLEADA plus ADT resulted in a trend toward longer time to PSA progression (HR, 0.56; 95% CI, 0.23-1.36; P=0.196), whereas treatment with ERLEADA alone resulted in a trend toward shorter time to PSA progression (HR, 1.09; 95% CI, 0.49-2.43; nominal P=0.824).
• Median TTTR was similar between the ADT and ERLEADA plus ADT groups (23.3 months vs 24.0 months, respectively).
  • In patients receiving ERLEADA, testosterone levels were supraphysiological during 12 months of treatment, consistent with the mechanism of action of ERLEADA, and returned to baseline by 24 months off treatment.
  • At 24 months, in the ERLEADA, ADT, and ERLEADA plus ADT groups, 90.9%, 90.0%, and 84.2% of patients, respectively, had serum testosterone levels >150 ng/dL (Table: Serum Testosterone Recovery [>150 ng/dL] at 24 Months with or without PSA Progression).
• At 12 months, no clinically relevant changes were observed in bone mineral density of the femoral neck or lumbar spine assessments in any treatment group.

• The prevalence of biomarkers associated with poor prognosis and aggressive phenotype was similar between baseline and end of study treatment (EOST).
  • A difference in prevalence between baseline and EOST was seen for biomarkers MYBPC1 (12.5% vs 22.2%), NPY (17.5% vs 25.9%), and PGR (2.5% vs 11.1%) transcripts.
  • EPHA3 expression, detected in 12 (30.0%) patients at baseline and 19 (35.2%) at EOST, was the only biomarker whose detection at baseline was associated with a significantly shorter time to PSA progression from pooled patients in all 3 treatment groups (P=0.02).
• The median time to PSA progression by assessed molecular classifiers is reported in Table: PSA Progression in Patients with Various Molecular Subtypes.

• Results from a post hoc analysis of PSA progression and TTTR have been described.¹²

Safety

• A summary of AEs is shown in Table: Summary of Treatment-Emergent AEs (Safety Population).

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 29 May 2024.