SUMMARY

• PRESTO (AFT-19) 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
• In 2 ongoing phase 3 studies (PRIMORDIUM^4-6 and INDICATE^7,8), the efficacy and safety of ERLEADA in patients with high-risk, prostate-specific membrane antigen positron emission tomography (PSMA-PET)-positive hormone-sensitive prostate cancer (HSPC) and prostate cancer with post-prostatectomy biochemical recurrence, respectively, are being evaluated. The safety and efficacy results have not been published.
• Phase 2 studies (STARTAR,⁹  FORMULA-509,¹⁰ and ARN-509-002¹¹) have evaluated the efficacy and safety of ERLEADA with various treatment regimens in patients with disease states including PSA recurrent prostate cancer and BRPC. These studies have reported outcomes including progression-free survival (PFS), metastasis-free survival (MFS), PSA levels, and health-related quality of life (HRQoL).
• 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.^12-14

Guidelines

• In the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Prostate Cancer, the following treatment options are noted in PROS-12:¹⁵
  • 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.¹⁵ 
• Please refer to the full Prescribing Information for ERLEADA (apalutamide) for information on INDICATIONS AND USAGE.¹⁶ 

^*Aggarwal R, et al. J Clin Oncol 2024;42:1114-1123.

CLINICAL DATA

Phase 3 Studies

PRESTO Study

Aggarwal et al (2024)² evaluated 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; NCT03009981).

Study Design/Methods

• Phase 3, randomized, open-label, multicenter study (Figure: PRESTO Study Design)

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.
• In an analysis evaluating HRQoL outcomes, no statistically significant mean changes from baseline to end of treatment were observed between the ERLEADA + ADT or ERLEADA + AAP + ADT vs ADT treatment arms in any HRQoL measure.¹⁸

Safety

• A summary of TEAEs at the first interim analysis is described in Table: Most Common TEAEs of Clinical Interest.
• Grade 4 hypertension was reported in 2 (1.2%) patients in the ERLEADA + AAP + ADT group.
• The most frequently reported grade ≥3 AE was hypertension in all groups.

• 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 (NCT04557059) is an ongoing 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. This study is not designed to compare results across cohorts.^4-6

Study Design/Methods

• Phase 3, randomized, open-label, multicenter, global study (Figure: PRIMORDIUM Study Design).

Results

Baseline Characteristics

• Baseline characteristics of enrolled patients through the data cutoff date of January 12, 2023 have been published.⁵
• Efficacy and safety results have not been published.

INDICATE Study

INDICATE (NCT04423211) is an ongoing study evaluating the use of ERLEADA in patients with prostate cancer with post-prostatectomy biochemical recurrence.^7,8

Study Design/Methods

• Phase 3, randomized, open-label study
• Patients in cohort 1 (positron emission tomography [PET]-negative) will be randomized to receive 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 receive SOC ST and ERLEADA with or without metastasis-directed radiation therapy (RT) to PET-positive lesions.

Results

• Efficacy and safety results have not been published.

Phase 2 Studies

STARTAR Study

Zhang et al (2025)⁹ evaluated combined treatment of ERLEADA and ADT for 9 months with external beam radiation therapy followed by 6 cycles of adjuvant docetaxel compared to the historical controls from the STREAM study in patients with PSA recurrent prostate cancer after radical prostatectomy (N=39; NCT03311555).

Study Design/Methods

• Phase 2, prospective, multicenter, single-arm, open-label study
• Patients received ADT for over 9 months and ERLEADA 240 mg orally daily for approximately 36 weeks.
• Beginning week 8, external beam radiation therapy at 64.8-68 Gy was administered to the prostate bed over 6-8 weeks, followed by a 4-week washout and then docetaxel 75 mg/m² IV every 3 weeks for up to 6 cycles.

Results

Patient Characteristics

• The median age in the overall population and the STREAM cohort (N=38) was 64 years (interquartile range [IQR], 60-67 and IQR, 59-69, respectively).
• The median baseline PSA in the overall population and the STREAM cohort was 0.58 ng/mL (IQR, 0.35-1.06) and 0.4 ng/mL (0.29-0.75), respectively.

Efficacy

• The median follow-up time for patients without progression was 37 months (IQR, 36-38).
• All patients who were evaluable for the primary endpoint were alive at the time of analysis, and all the patients (100%) achieved undetectable PSA as PSA nadir on treatment.
• The 2- and 3-year PFS were 84% and 71%, respectively; this improved significantly over the 3-year PFS of 47% in the historic control in the multimodality trial and 54% in the STREAM treatment cohort (P=0.004 and P=0.039, respectively).
• Testosterone recovery was reported in 4 (11%), 31 (82%), and all 37 patients at 1 year, 2 years, and data lock, respectively.
• PSA of <0.1 ng/mL with testosterone recovery was reported in 38%, 67%, and 69% of patients at 1, 2, and 3 years, respectively.
• The median time to testosterone recovery was 15 months (95% CI, 13-17).

Safety

• The most common AEs (>30%) included hot flashes (97%), fatigue (87%), alopecia (77%), anemia (59%), dysgeusia (59%), maculopapular rash (54%), diarrhea (44%), urinary frequency (44%), nausea (41%), insomnia (38%), urinary urgency (36%), paresthesia (36%), dyspnea (33%), pruritus (31%), and edema (31%).
• The maximum hematologic grade 3-4 AEs were neutropenia (27 [69%]), including 3 febrile neutropenia events during chemotherapy.
• Serious AEs observed included febrile neutropenia (3 [8%]) and 1 (2.6%) each of: flu-like symptoms/sinus tachycardia, fever, pelvic infection, hematoma, and thromboembolism.
• Among patients who dose reduced or discontinued any part of study treatments, ERLEADA was held or dose reduced for 10 (25%) patients, with 2 (5%) patients discontinuing; docetaxel was held or dose reduced for 7 (18%) patients, with another 10 (25%) discontinuing; and radiation was held for 1 (3%) patient.
• The median number of docetaxel cycles received was 6, with 23 (62%) patients completing all 6 planned cycles of docetaxel. Some of these remaining 16 patients discontinued docetaxel early due to toxicity, but some discontinued early due to the COVID-19 pandemic out of precaution for immune suppression.

FORMULA-509 Study

FORMULA-509 (NCT03141671) 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).¹⁰

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.

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

ARN-509-002 (NCT01790126) 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).¹¹

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).

Results

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.
• 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). This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.
• 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.
• 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).
• Results of median time to PSA progression by assessed molecular classifiers and a post hoc analysis of PSA progression and TTTR have been described.

Safety

• A summary of AEs is shown in Table: Summary of Treatment-Emergent AEs (Safety Population).
• The most frequently reported AE was fatigue in all arms (ERLEADA: 65.5%; ADT: 75.9%; ERLEADA + ADT: 77.4%).
• One (3.4%) patient receiving ADT experienced a fatal event of toxic epidermal necrolysis.

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 08 May 2025.