Metacure: Multi-arm Multi-modality Therapy for Very High Risk Localized and Low Volume Prostatic Adenocarcinoma

The purpose of this study is to test if treatment with medications that reduce the male
hormone level in the participant's body for a few months before surgery can shrink
prostate cancer as much as possible, which might reduce the chances of the cancer coming
back in the future. These treatments include a hormone injection given monthly or every
three months and the study drugs, which include abiraterone acetate, prednisone, and
apalutamide.

These medications are being used in combination with surgery and maybe radiotherapy
because studies have shown that any single approach on its own is not sufficient to
control or get rid of the cancer especially if they have high risk or aggressive
features. The researchers hope to learn if combining the study drugs with surgery and
radiation will get rid of the cancer from participants' prostates and reduce their
prostate-specific antigen (PSA) to an undetectable level.

Inclusion Criteria:

- Willing and able to provide written informed consent and Authorization for Use and
Release of Health and Research Study Information (HIPAA authorization) NOTE: HIPAA
authorization may be either included in the informed consent or obtained separately

- Male aged 18 years and above

- Serum testosterone of ≥150 ng/dL (For Cohorts A and B1, testosterone level
requirement is exempted if they are already on ADT prior to treatment start. For
Cohort B2, subjects will be considered eligible if their testosterone is currently
≥150 ng/dl).

- Histologically confirmed adenocarcinoma of the prostate, who meet the following
criteria:

Cohort A

- Clinically localized disease with histologically confirmed adenocarcinoma of the
prostate with either ≥3 positive cores or 2 positive cores if >1cm in length with at
least 50% tumor content WITH

- With Gleason score 8-10 OR

- Gleason 4+3 with one of the following features:

- PSA ≥ 20 mg/mL within 2 months prior to diagnostic biopsy

- MRI suspicious for radiographic ≥T3 disease (if urologist deems tumor is resectable
at baseline); defined as >75% probability of extracapsular extension or seminal
vesicle invasion in the opinion of the reading radiologist.

OR

- Gleason 3+4 or 4+3 and Oncotype DX Genomic Prostate Score of >40

- With or without clinical N1 (size >1.5cm in the short axis) (Gleason score
requirement can be omitted if node positive)

OR

Cohort B1

- Newly diagnosed low-volume metastatic disease with either.

- Bone metastases as documented by CT, MRI or radionuclide bone scan amenable to
treatment with a maximum of 3 radiation isocenters* These lesions must have a
structural correlate on CT or MRI to allow for adequate radiation targeting

*(note:subjects with PET scans that show osseous metastases that would not be
amenable to 3-isocenter radiation treatment are still eligible if conventional
imaging shows osseous disease that can be treated with 3 radiation isocenters)
And/or

- Retroperitoneal nodes up to the level of the renal hilum with/without pelvic nodal
metastasis >1.5cm in the short axis

OR

Cohort B2 (Cohort B2 expansion)

- Biochemically persistent/recurrent disease (defined as PSA >0.2) after RP ± extended
pelvic nodal dissection identified on PSMAb PET scans

- PSMA PET evidence of M1a/M1b disease that could be covered in up to 3 radiation
plans (note that the isocenter for planned prostate bed/pelvic nodal irradiation
does not count towards the 3 isocenter limit)

- No radiographic evidence of local or regional recurrence on imaging in subjects with
prior salvage radiation to these areas.

- Prior salvage radiotherapy is permitted. Prior metastasis-directed radiation is not
permitted.

- Castration sensitive disease

- Multiple lesions within one isocenter may be permitted upon review by the sponsor's
radiation oncologist

- ECOG performance status of ≤ 1

- Adequate bone marrow, hepatic and renal function, as evidenced within 28 days prior
to treatment start by:

- ANC ≥ 1500/µl

- Hemoglobin ≥ 9g/dL

- Platelet count ≥ 100,000/µl

- Serum Creatinine GFR ≥30 mL/min

- Porassium within institutional normal range

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

- Albumin ≥ 3.0 g/dL

- SGOT (AST) ≤ 2.5 x ULN

- SGPT (ALT) ≤ 2.5 x ULN

- Subjects must have a clinical T stage documented by the treating urologist/medical
oncologist within 90 days prior to treatment start using the 7th edition AJCC
staging system, recorded as the urologist's/medical oncologist's best clinical
assessment of extent of local disease by digital rectal examination and/or available
imaging studies such as transrectral ultrasound, CT scan, and/or MRI. Applicable to
Cohort A and B1.

- The primary tumor must be considered unresectable by RP based on initial imaging
with gross negative margins as determined by a urologist and documented as such.
(applicable to Cohorts A and B1 only)

- Recovery of reversible effects of prior surgery (i.e., incisional pain, wound
drainage) to Grade ≤1, and at least 4 weeks from prior surgery to treatment start.
(biopsy excluded)

- Able to swallow the study drug(s) whole as a tablet

- Willing to take abiraterone acetate on an empty stomach; no food should be consumed
at least one hour before and for at least two hours after the dose of abiraterone
acetate is taken (Note: apalutamide does not have to be taken on an empty stomach.)

- 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.

- For Cohorts B1 and B2 only, biopsy confirmation of metastases (strongly encouraged;
if safe and feasible at treating center)

Exclusion Criteria:

- Prior treatment for prostate cancer including prior surgery (excluding TURP and
subjects with rising PSA after RP), pelvic lymph node dissection, radiation therapy
unless the subject is eligible for Cohort B2.

- Prior cytotoxic chemotherapy or biologic therapy for prostate cancer

- Up to 2 months of prior ADT with GnRH antagonist/agonist at time of treatment start.
Bicalutamide given for ≤ 12 months at the time of registration as flare prevention
is allowed. For Cohort B2, prior ADT and/or first generation anti-androgen treatment
in the (neo)adjuvant and/or salvage setting in conjunction with radiation or surgery
is allowed provided last effective dose of ADT and/or first generation anti-androgen
is > 12 months prior to the on treatment date and total duration of prior therapy is
12 months or lesser, and their testosterone is currently >150ng/dL.

- Prior exposure to ketoconazole (systemic), abiraterone acetate, enzalutamide or
other agents targeting the AR signaling pathway

- Concomitant therapy with any other experimental drug

- Known brain, liver, lung or other visceral metastasis (except for retroperitoneal
and / or pelvic nodal metastases as per inclusion criteria)

- Prior prostate cancer metastasis-directed therapies

- Currently active second malignancy or past history of malignancies diagnosed within
the last 2 years that require active therapy and/or in remission with life
expectancy of < 5 years, with the exception of resected non-melanoma skin cancers,
non-muscle invasive bladder cancer, state I head and neck cancer, or stage I
colorectal cancer

- Significant medical condition other than cancer, that would prevent consistent and
compliant participation in the study that would, in the opinion of the investigator,
make this protocol unreasonably hazardous including but not limited to:

- Any medical condition requiring a higher dose of corticosteroid than 10mg
prednisone/prednisolone once daily

- Active infection requiring systemic therapy

- History of gastrointestinal disordered (medical disorders or extensive surgery)
that may interfere with the absorption of the study agents

- Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg);
subjects with a history of hypertension are allowed provided blood pressure is
controlled by anti-hypertensive treatment (systolic BP < 160 mmHg or diastolic
BP <95 mmHg)

- Active or symptomatic viral hepatitis of chronic liver disease

- Acute or chronic hepatitis B or hepatitis C infection. (Hepatitis B and C
testing are not mandatory)

- Presence of hepatitis B surface antibody is acceptable

Human immunodeficiency virus (HIV)-positive subjects with 1 or more of the following:

Not receiving highly active anti-retroviral therapy. A change in anti-retroviral therapy
within 6 months of the start of screening (except if, after consultation with the
principal investigator (PI) / sponsor, a change is made to avoid a potential drug-drug
interaction with the study drug).

Receiving anti-retroviral therapy that may interfere with the study drug(s) (consult the
PI / sponsor for review of medication prior to enrollment).

CD4 count < 350 cell/mm^3 at screening. An acquired immunodeficiency syndrome-defining
opportunistic infection within 6 months of the start of screening.

- History of pituitary or adrenal dysfunction

- History of hypogonadism

- Clinically significant heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or New
York Heart Association (NYHA) Class III or IV heart disease or cardiac ejection
fraction measurement of <50% at baseline, or clinically significant ventricular
arrhythmias within 6 months prior to treatment start.

- History of seizure or any condition that may predispose to seizure (including, but
not limited to prior stroke, transient ischemic attack or loss of consciousness 1 year prior to treatment start; brain arteriovenous malformation; or intracranial
masses such as schawnnomas and meningiomas that are causing edema or mass effect)

- Uncontrolled diabetes mellitus

- History of inflammatory bowel disease

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

- Use of any prohibited concomitant medications within 14 days prior to treatment
start, or use of prohibited concomitant medication listed in section 7.9.1
within the outlined windows NOTE: Medications known to lower the seizure
threshold must be discontinued or substituted at least 4 weeks prior to
treatment start

- Pre-existing condition that warrants long-term corticosteroid use in excess of
10 mg prednisone/prednisolone daily

- Known allergies, hypersensitivity or intolerance to apalutamide, abiraterone
acetate, prednisone, or GBRH agonist or GNRH antagonist

- Administration of an investigational therapeutic within 30 days of treatment
start

- Patients that cannot tolerate MRI

- Any condition which, in the opinion of the investigator, would preclude
participation in this trial