Apalutamide Plus Intermittent Hormone Therapy Versus Intermittent Hormone Therapy Alone in Prostate Cancer

Prostate-specific antigen (PSA) is a sensitive and specific biomarker of prostate tissue.
Monitoring of PSA after local treatment for prostate cancer can assist in identifying
patients who have only increased PSA (biochemical recurrence [BCR]) despite no symptoms,
signs, or evidence of radiographic metastatic disease. This subpopulation of patients are
referred to as having "biochemical failure." Androgen deprivation therapy (ADT) is a standard
treatment option, but is only effective for 16-24 months and has a number of side effects
that impact quality of life. These side effects may include fatigue, hot flushing, loss of
sex drive, brain fog, decreased bone mineral density, loss of muscle mass, mild anemia,
diabetes, heart disease, metabolic syndromes and risk of fractures. An alternative to
continuous ADT is intermittent administration, where patients are given "breaks" from ADT to
let their testosterone levels return to baseline. There are a number of potential benefits to
intermittent hormone therapy (IHT): (1) longer time to the development of resistance, owing
to the removal of constant pressure causing faster mutation of resistant cells; (2) improved
patient quality of life owing to recovery from adverse effects, particularly sexual function;
and (3) substantial cost savings owing to less time spent receiving medication. Leuprolide is
the name of the ADT / IHT drug.

Apalutamide is an investigational antitumor drug, taken by mouth. It is a synthetic compound
rationally designed to bind the androgen receptor (with higher affinity than enzalutamide or
bicalutamide), prevent both nuclear translocation and DNA binding, and induce apoptosis. It
has greater antitumor activity at a lower dose, achieves steady-state levels at a lower dose,
and accumulates more into tumor tissue without building up in the brain, which both increases
effectiveness and decreases the risk of seizure.

Apalutamide's mechanism of action gives it the potential to extend the time to PSA increase
during intermittent ADT, delaying the necessity for continuous ADT. Investigators will assess
the potential applications of intermittent ADT plus Apalutamide for participants with BCR.
This study will elucidate the potential of this regimen to reduce the burden of adverse
events of continuous ADT and delay the development of hormone resistance.

This is a randomized crossover study intended to determine the interval of ADT administration
achievable with supportive Apalutamide treatment. Investigators will assess the significance
of time to PSA recurrence, time to next leuprolide injection, time to testosterone recovery,
duration of testosterone recovery, time to biochemical recurrence, percentage of men
developing biochemical recurrence, number of detectable CTCs, and quality of life measures.

Treatment will be 66 participants in 2:1 randomized crossover - 45 IHT + apalutamide:21 IHT
only until second leuprolide injection, then IHT + apalutamide

Apalutamide + IHT Participants will be treated with 240 mg (4 60 mg tablets) oral Apalutamide
daily plus 22.5 mg 3-month depot intramuscular leuprolide intermittently.

IHT Participants will receive 22.5 mg 3-month depot intramuscular leuprolide until PSA
progression, when they will receive 240 mg oral Apalutamide daily plus 22.5 mg 3-month depot
intramuscular leuprolide intermittently.

Participants remain on study until continuous ADT is required to maintain castrate PSA levels
(i.e., leuprolide is needed every 3 months to maintain PSA <1 ng/dL).

Inclusion Criteria:

- Age ≥ 18 years

- Patients with a diagnosis of adenocarcinoma of the prostate

- Patients with BCR (PSA becomes detectable, with absolute value ≥1) following
prostatectomy who have no evidence of metastatic disease based on radiographic
assessment.

- Patients with BCR following radiation therapy who have no radiographic involvement per
mpMRI and CT (RTOG-ASTRO Phoenix criteria), size of pelvic nodes ≤1 cm, and whose
MRI-directed prostate biopsies are negative.

- Patients must be free of serious comorbidity as determined by investigator.

- Clinical laboratory values at screening:

- Serum testosterone level ≥150 ng/dL

- Hemoglobin ≥9.0 g/dL, independent of transfusion and/or growth factors within 3 months
prior to randomization

- Platelet count ≥100,000 /µL independent of transfusion and/or growth factors within 3
months prior to randomization

- Serum albumin ≥3.0 g/dL

- GFR >45 mL/min

- Serum potassium ≥3.5 mmol/L

- Serum total bilirubin ≤1.5 × ULN (Note: In subjects with Gilbert's syndrome, if total
bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin
is ≤1.5 × ULN, subject may be eligible)

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 × ULN

- Medications known to lower the seizure threshold (see list under prohibited meds,
Appendix 3) must be discontinued or substituted at least 4 weeks prior to study entry.

- Agrees to use a condom (even men with vasectomies) and another effective method of
birth control if he is having sex with a woman of childbearing potential or agrees to
use a condom if he is having sex with a woman who is pregnant while on study drug and
for 3 months following the last dose of study drug. Must also agree not to donate
sperm during the study and for 3 months after receiving the last dose of study drug.

- Written, informed consent to participate in this study.

Exclusion Criteria:

- PSA doubling time >12 months

- Positive for HIV or chronic hepatitis B or hepatitis C infection

- Another primary malignancy that has not been in remission for at least 2 years.
Non-melanoma skin cancer allowed.

- Use of herbal products that may decrease PSA levels (e.g., saw palmetto) or systemic
corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4
weeks of screening laboratory studies.

- Any other condition, including concurrent medical condition, social circumstance or
drug dependency, which in the opinion of the investigator could compromise patient
safety and/or compliance with study requirements

- History of any of the following:

- Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke
within 1year to randomization, brain arteriovenous malformation, Schwannoma,
meningioma, or other benign CNS or meningeal disease which may require treatment
with surgery or radiation therapy)

- Severe or unstable angina, myocardial infarction, symptomatic congestive heart
failure, arterial or venous thromboembolic events (eg, pulmonary embolism,
cerebrovascular accident including transient ischemic attacks), or clinically
significant ventricular arrhythmias within 6 months prior to randomization Any
condition that in the opinion of the investigator, would preclude participation
in this study

- Current evidence of any of the following:

- Uncontrolled hypertension

- Gastrointestinal disorder affecting absorption

- Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis) Any
condition that in the opinion of the investigator, would preclude participation
in this study