Details

IRB Study Number 19-525

Status Active, not recruiting

Location Cleveland Clinic Main Campus

Institute Taussig Cancer Institute

Description

Description

Primary Objective

  • 1The proportion of patients with a pCR + MRD (≤ 5mm tumor) in the prostate in patients undergoing RP (cohorts A and B1).

Secondary Objectives

  • Elimination of metastatic disease evidenced by an undetectable PSA (<0.1ng/mL) following testosterone recovery (PSA0) at 24 months from the start of ADT stratified by the presence of metastasis at enrollment (i.e., M0 vs M1) for Cohorts A + B1 + B2.
  • Proportion of patients with pCR in the prostate.
  • PSA response rate defined as percentage of patients with an undetectable PSA at 10 months from treatment start (after the completion of therapy with castrate levels of testosterone)
  • Time to PSA progression defined as the time from the start of treatment to the date of first evidence of disease progression (serum PSA ≥0.2ng/mL, which is confirmed by a second determination with a PSA ≥0.2 ng/mL, according to the 2007 American Urological Association Prostate Guidelines). It is expected that the majority of patients will relapse biochemically with a rising PSA.
  • Quality of life
  • Time to and frequency of testosterone recovery
  • Systemic therapy-related toxicity rates

Inclusion Criteria

Inclusion Criteria

  1. 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
  2. Male aged 18 years and above
  3. 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, patients will be considered eligible if their testosterone is currently ≥150 ng/dl). Clinical phenotypes as described in either one of the following cohorts:
    • 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
    • Gleason score 8 - 10 or
    • Gleason 4+3 or 3+4 with one of the following features:
    • PSA ≥20 ng/mL within 2 months prior to diagnostic biopsy
    • MRI suspicious for radiographic ≥T3 disease (as long as 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/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 in order to allow for adequate radiation targeting (note: patients with PET scans that show osseous metastases that would not be amenable to 3-isocenter radiation treatment are still eligible as long as 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 >1.5 cm in the short axis OR
    • Cohort B2
    • Rising PSA after RP with:
    • Osseous or retroperitoneal nodal metastases (up to the level of renal hila) as documented by FACBC or PSMA PET which are:
    • amenable to treatment with a maximum of 3 radiation isocenters These lesions should have structural correlates on CT or MRI. Lesions without structural correlates will be viewed as equivocal and not need to be irradiated but will be followed.
    • With associated CT or MRI correlate
    • No evidence of local recurrence within prior radiation field on MRI or other imaging studies i.e. local recurrence is acceptable in patients without prior salvage radiation.
    • Prior salvage radiotherapy is permitted.
    • Multiple lesions within one isocenter may be permitted upon review by the sponsor's radiation oncologist;
    • ECOG performance status of ≤ 1 (Appendix A)
  1. Adequate bone marrow, hepatic, and renal function, as evidenced within 28 days prior to treatment start by: (See protocol)
  2. Patients 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 transrectal ultrasound, CT scan, and/or MRI. Applicable to Cohort A and B1.
  3. The primary tumor must be considered resectable 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)
  4. 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)
  5. Able to swallow the study drug(s) whole as a tablet.
  6. 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.)
  7. 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.
  8. For Cohorts B1 and B2 only, biopsy confirmation of metastases (strongly encouraged; if safe and feasible at treating center)

Exclusion Criteria

Exclusion Criteria

  1. Prior treatment for prostate cancer including prior surgery (excluding TURP and patients with rising PSA after RP), pelvic lymph node dissection, radiation therapy unless the patient is eligible for Cohort B2.
  2. Prior cytotoxic chemotherapy or biologic therapy for prostate cancer
  3. More than 2 months of prior ADT with GnRH antagonist/agonist at time of treatment start. Bicalutamide given for < 2 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 date of randomization and total duration of prior therapy is 12 months or lesser, and their testosterone is currently >150ng/dL
  4. Prior exposure to ketoconazole (systemic), abiraterone acetate, enzalutamide or other agents targeting the AR signaling pathway.
  5. Concomitant therapy with any other experimental drug
  6. Known brain, liver, lung or other visceral metastasis (with the exception of retroperitoneal and / or pelvic nodal metastases as per inclusion criteria)
  7. Prior prostate cancer metastasis-directed therapies
  8. Currently active second malignancy or past history of malignancies diagnosed within the last 5 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, stage I head and neck cancer, or stage I colorectal cancer.
  9. 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
    • History of gastrointestinal disorders (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); patients 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 or chronic liver disease
    • Known active HIV, Hepatitis B or Hepatitis C infection. (HIV testing is not mandatory)
    • 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 schwannomas 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)
  1. Use of any prohibited concomitant medications (Appendix B) within 14 days prior to treatment start, or use of prohibited concomitant medications 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
  2. Pre-existing condition that warrants long-term corticosteroid use in excess of 10 mg prednisone/prednisolone daily. (Note: Per Section 7.2, if a subject has been receiving glucocorticoids other than prednisone or prednisolone, it will be necessary to switch the glucocorticoids to prednisone or prednisolone 5 mg twice daily prior to Day 1.)
  3. Known allergies, hypersensitivity or intolerance to apalutamide, abiraterone acetate, prednisone, or GNRH agonist or GNRH antagonist
  4. Administration of an investigational therapeutic within 30 days of treatment start
  5. Patients that cannot tolerate MRI
  6. Any condition which, in the opinion of the investigator, would preclude participation in this trial