A Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer

Patients will be stratified by PSA doubling time (< 3 months vs. 3-9 months) and randomized
in 1:1:1 fashion to one of three treatment arms: (1) Control arm consisting of degarelix
monotherapy, (2) Experimental arm consisting of apalutamide in combination with degarelix,
and (3) Experimental arm consisting of apalutamide, abiraterone acetate + prednisone, and
degarelix. Patients will be treated for a maximum duration of 52 weeks and then enter follow
up phase until the time of PSA progression, development of metastasis, or patient withdrawal
from study, whichever occurs first. Patients with PSA progression will be followed long term
until the development of castration resistance, first metastasis, and death.

The primary endpoint of the study is PSA progression-free survival in the intent-to-treat
patient population. PSA progression during the 52-week treatment period is defined as a
rising PSA confirmed on repeat measurement, and at least 25% and 2 ng/mL above nadir or
baseline, whichever is lower. PSA progression during follow up defined as PSA > 0.2 ng/mL
confirmed by repeat measurement at least 2 weeks later. Secondary study endpoints include PSA
progression-free survival in testosterone-evaluable population, 36-month PSA progression-free
survival rate in both intent-to-treat and testosterone-evaluable populations, time to
testosterone recovery, time to castration resistance, metastasis-free survival, quality of
life, and safety. Each experimental arm will be compared against the control arm in pair-wise
fashion. The study is not powered to detect differences in primary or secondary endpoints
between the two experimental arms.

Inclusion Criteria:

- Histologically confirmed prostate adenocarcinoma

- Prior radical prostatectomy

- Biochemically recurrent prostate cancer with PSA doubling time ≤ 9 months at the time
of study entry. Calculation of PSA doubling time should include the use of all
available PSA values obtained within past 12 months prior to randomization, with a
minimum of 3 values separated by at least 2 weeks apart. PSA values obtained prior to
localized therapy will be excluded. PSA doubling time to be estimated using Memorial
Sloan Kettering Cancer Center online calculator
(https://www.mskcc.org/nomograms/prostate/psa-doubling-time)

- Prior adjuvant or salvage radiation or not a candidate for radiation based upon
clinical assessment of disease characteristics and patient co-morbidities.

- Screening PSA > 0.5 ng/mL

- No definitive evidence of metastases on screening CT or MRI of abdomen/pelvis and
radionuclide whole body bone scan per the judgment of the investigator. Abdominal
and/or pelvic lymph nodes measuring 2 cm or less in short axis diameter are allowed.
Lesions identified on other imaging modalities (e.g. PSMA or choline PET) that are not
visualized on CT and/or MRI or radionuclide bone scan are allowed. Equivocal lesions
on bone scan should be followed up with additional imaging as clinically indicated.

- Screening serum testosterone > 150 ng/dL

- Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1

- Age ≥ 18 years

- Medications known to lower the seizure threshold (see Appendix 1) 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.

- Adequate organ function as defined by the following laboratory values at screening:

- Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase
[SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase
[SGPT]) < 2.5 x upper limit of normal (ULN)

- Total serum bilirubin ≤1.5 x ULN. 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)

- Serum potassium ≥ 3.5 mmol/L. Supplementation and re-screening is allowed.

- Estimated GFR > 45 ml/min using Cockroft-Gault equation

- Platelets ≥ 100,000/microliter independent of transfusion and/or growth factors
within 3 months prior to randomization

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

- Serum albumin ≥ 3.0 g/dL

Exclusion Criteria:

- Prior androgen deprivation therapy and/or first generation anti-androgen (e.g.
bicalutamide, nilutamide, flutamide) for biochemically recurrent prostate cancer.
Prior ADT and/or first generation anti-androgen in the (neo)adjuvant and/or salvage
setting before, during, and/or following radiation or surgery is allowed provided last
effective dose of ADT and/or first-generation anti-androgen is > 9 months prior to
date of randomization and total duration of prior therapy is ≤ 36 months.

- Prior treatment with CYP17 inhibitor (e.g. ketoconazole, abiraterone acetate,
galeterone) or second generation androgen receptor antagonist including apalutamide or
enzalutamide

- Prior chemotherapy for prostate cancer except if administered in neoadjuvant or
adjuvant setting

- Use of 5-alpha reductase inhibitor within 42 days prior to randomization

- Use of investigational agent within 28 days prior to randomization

- Use of other prohibited medications within 7 days prior to cycle 1 day 1 on study
(Arms B and C only) (see Appendix 1 for list of prohibited medications)

- Prior bilateral orchiectomy

- 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)

- Uncontrolled hypertension

- Gastrointestinal disorder affecting absorption or the ability to swallow tablets

- Baseline severe hepatic impairment (Child-Pugh Class B & C)

- Intercurrent illness that is not controlled such as active infection, psychiatric
illness/social situations that would limit compliance with study requirements

- Any chronic medical condition requiring a higher dose of corticosteroid than
equivalent of 5 mg prednisone/prednisolone once daily