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 (BCR) prostate cancer 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; HR, 0.52; 95% 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).¹
  • 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
  • In an analysis evaluating health-related quality of life (HRQoL) outcomes, no statistically significant mean changes from baseline to end of treatment (EOT) were observed between the ERLEADA + ADT or ERLEADA + AAP + ADT vs ADT treatment arms in any HRQoL measure.⁴
  • 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
  • Post hoc analyses evaluating the sensitivity of PSA-PFS, association of baseline factors with PSA-PFS, time to testosterone recovery (TTTR) after treatment completion, PSA-PFS in the strata of <3 months or 3-9 months PSADT at study entry, and association between PSA nadir within the first 3 months of treatment with subsequent PSA-PFS have been conducted.^1,5,6

Guidelines

• In the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Prostate Cancer, the following treatment options are noted in PROS-12:⁷
  • 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.⁷
• Please refer to the full Prescribing Information for ERLEADA (apalutamide) for information on INDICATIONS AND USAGE.⁸

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

CLINICAL DATA

Aggarwal et al (2024)¹ 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).

Study Design/Methods

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

PRESTO Study Design^1,2,9Abbreviations: AAP, abiraterone acetate plus prednisone; ADT, androgen deprivation therapy; AE, adverse event; BID, twice daily; BRPC, biochemically relapsed prostate cancer; PFS, progression-free survival; PO, orally; PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time; QD, once daily; RP, radical prostatectomy; TTTR, time to testosterone recovery.^aPrior ADT and/or first-generation antiandrogen (eg, bicalutamide, nilutamide, flutamide) in the neoadjuvant and/or salvage setting before, during, and/or following radiation or surgery was permitted provided the last effective dose was >9 months prior to randomization and total duration was ≤36 months.^bLuteinizing hormone-releasing hormone analog (degarelix or leuprolide with bicalutamide) per investigator discretion.^cDefined 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 and confirmed on repeat measurement ≥2 weeks later.^dDefined as the subset of patients who recovered serum testosterone to >50 ng/dL during follow-up.^eAt the time of PSA progression, patients were followed long term with treatment administered per the investigator’s discretion.

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 to 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 EOT were evaluated across the 3 treatment arms (Table: Mean Changes in HRQoL From Baseline to EOT).⁴
• 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 for each HRQoL measure between treatment arms did not meet the published minimally clinically important difference thresholds.

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.

Post Hoc Analyses

Analyses of PSA-PFS

• A post hoc sensitivity analysis of PSA-PFS with an additional year of follow-up was conducted (Table: PSA-PFS Sensitivity Analysis).

• A post hoc subgroup analysis evaluated PSA-PFS in the strata of <3 months or 3‑9 months PSADT at study entry (Table: PSA-PFS by PSADT at Study Entry).

• A post hoc univariate analysis evaluated baseline factors associated with PSA-PFS across the entire study cohort (Table: Association of Baseline Gleason Grade With PSA-PFS).^1,5

Testosterone Recovery

• A post hoc analysis evaluated TTTR to >150 and 280 ng/dL after treatment completion (Table: Post Hoc Analysis of TTTR).

PSA

• A post hoc analysis evaluated the association between PSA nadir within the first 3 months of treatment with subsequent PSA-PFS among 463 evaluable patients across the 3 treatment arms (Table: Association Between PSA Nadir and PSA-PFS).⁶

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 27 May 2024.