A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Apalutamide in Subjects with High-risk, Localized or Locally Advanced Prostate Cancer Who are Candidates for Radical Prostatectomy

High-risk prostate cancer accounts for approximately 15% of newly diagnosed
prostate cancers. For patients with high-risk, locally advanced prostate
cancer, prostatectomy alone may be inadequate therapy. Cure rates from
prostatectomy alone are less than 30%. High-risk patients experience the
highest recurrence after prostatectomy, with disease progression rates of
approximately 50%. Patients with recurring disease after local therapy require
salvage therapy, which is associated with morbidity with detrimental impact on
quality of life. In a retrospective analysis of 379 men who developed a
biochemical recurrence after radical prostatectomy, it was found that patients
with a Gleason score of 8 to 10 were more likely to die from prostate cancer
than patients with a Gleason score of 7 or less.

Several de*nitions of high-risk prostate cancer are used in the urological
literature. Patients with high-risk localized or locally advanced prostate
cancer include those with Gleason scores >=8, clinical stage >=cT2c (disease in
both or extension outside of the lobes), high baseline prostate specific
antigen (PSA; >=20 ng/mL), or involvement of regional nodes. For the current
study, high risk is defined by histology and PSA, appropriate for a study in
candidates for RP with pLND.

In the early 1990s, studies of neoadjuvant ADT (commonly 3 months of treatment
with luteinizing hormone-releasing hormone agonists alone or with
antiandrogens) conducted primarily in lower risk patients showed some benefits
(eg, lower positive surgical margin rates or tumor downstaging). However, these
were generally smaller studies with a limited duration of follow up, so no
significant improvements were observed in survival. As such, neoadjuvant ADT
prior to radical prostatectomy has not been adopted as standard of care. With
the approval of next-generation AR signaling inhibitors, 4 neoadjuvant studies
with 6 months of androgen blockade prior to radical prostatectomy have been
completed. In these studies, the addition of 6 months of neoadjuvant therapy
improved local disease control at the time of radical prostatectomy.
Specifically, in patients with initially unresectable (cT3), locally advanced,
and high-risk prostate cancer (Gleason score >8 or PSA >20 ng/mL), the use of 6
months of neoadjuvant ADT with abiraterone acetate was associated with a
reduction in androgen concentration in the prostate tissue and this correlated
with fewer patients with a positive surgical margin, an increase in pCR, and
minimal residual disease without major peri- or postoperative complications.
Patients who received neoadjuvant abiraterone acetate and ADT also had lower
PSA relapse after a median follow-up of 3.5 years, and as a group, required
fewer subsequent therapies for prostate cancer. Six months of AAP with ADT in
the neoadjuvant setting was better than 3 months of AAP and ADT (Clinical
Trials.gov NCT00924469). Outcomes with 6 months of hormonal therapy have also
been shown to be better than 1 or 3 months of neoadjuvant therapy in a
correlative imaging study, supportive of the improvement observed in pathologic
outcome. Other studies evaluating next-generation hormone therapy in the
neoadjuvant setting are ongoing, including treatment with abiraterone acetate
and prednisone plus ADT or enzalutamide plus ADT (ClinicalTrials.gov
NCT02160353; NCT02028988; NCT01717053; NCT02023463), and in a neoadjuvant Phase
2 study with apalutamide plus ADT (ClinicalTrials.gov NCT03124433).

For adjuvant use of ADT, prospective randomized studies have shown that early
use of long term ADT extends survival, compared with treatment that is delayed
until disease progression. In a randomized study in 100 patients to determine
whether immediate ADT extends survival in patients with node positive prostate
cancer who have undergone radical prostatectomy and pelvic lymphadenectomy
compared with those who received ADT only at disease progression, it was shown
that early ADT benefits patients as compared to deferred treatment. Studies
evaluating next generation hormone therapy in the adjuvant setting include an
ongoing Phase 2 study evaluating enzalutamide after radical prostatectomy
(ClinicalTrials.gov NCT01927627 2017).

This study has been transitioned to CTIS with ID 2023-506153-38-00 check the CTIS register for the current data.

The purpose of this study is to determine if treatment with apalutamide plus
androgen deprivation therapy (ADT) before and after radical prostatectomy (RP)
with pelvic lymph node dissection (pLND) in participants with high-risk
localized or locally advanced prostate cancer results in an improvement in
pathological complete response (pCR) rate and metastasis free survival (MFS)
based on conventional imaging, as compared to placebo plus ADT.

This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter
study.

All subjects will receive background treatment with ADT. Treatment with study
medication will begin on Cycle 1 Day 1. Treatment will stop for radical
prostatectomy and resume approximately 2 weeks post surgery. The
investigational group will receive ADT plus apalutamide daily, and the control
group will receive ADT plus placebo(s) daily as described below.

Apalutamide/matching placebo. 240 mg (4 x 60 mg tablets) Once daily

An Independent Data Monitoring Committee (IDMC) will be commissioned for this
study. The IDMC will review the safety and efficacy data during the study and
make recommendations as to the further conduct of the study.