PRIMARY OBJECTIVE:
I. Efficacy of apalutamide in combination with abiraterone acetate + prednisone following
docetaxel with ongoing androgen deprivation therapy in men with high risk metastatic
castration sensitive disease.
SECONDARY OBJECTIVES:
I. Safety and tolerability of apalutamide in combination with abiraterone acetate +
prednisone following docetaxel with ongoing androgen deprivation therapy.
II. Time to event.
III. Depth of prostate specific antigen (PSA) response.
EXPLORATORY OBJECTIVES:
I. Quality of life.
II. Falls.
III. Molecular changes from prostate cancer over time.
OUTLINE:
Patients receive apalutamide orally (PO) once daily (QD), abiraterone acetate PO QD, and
prednisone PO QD. Cycles repeat every 4 weeks in the absence of disease progression or
unacceptable toxicity. Patients also receive androgen deprivation therapy per standard of
care.
After completion of study treatment, patients are followed up every 6 months for up to 10
years.
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed prostate cancer OR a
strong suspicion of prostate cancer as evidenced by metastatic disease in a pattern
consistent with prostate cancer (such as blastic lesions on a nuclear medicine bone
scan or lymphadenopathy on the computed tomography [CT] scan) AND a PSA > 50 ng/mL
- High risk disease (defined as meeting 2 of the 3: (1) visceral metastatic disease, (2)
3 or more bone lesions, (3) Gleason 8-10) at the time diagnosed metastatic
- If a patient has received androgen deprivation therapy (ADT) for neoadjuvant or
adjuvant therapy at least 24 months MUST have elapsed since its use to day 1 of
restarting ADT for metastatic castration sensitive disease
- ADT sensitive disease- no evidence of rising PSA or new metastatic deposits since
starting ADT
- Have completed up to 6 cycles of docetaxel since developing metastatic castration
sensitive disease with no more than 12 weeks elapsed since day 21 of the final cycle
- All races and ethnic groups will be included
- Life expectancy of greater than 18 months
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Hemoglobin > 9.0 g/dL, independent of transfusion and/or growth factors
- Leukocytes > 3,000/uL
- Absolute neutrophil count > 1,500/uL
- Platelets >= 100,000 x 10^9/uL, independent of transfusion and/or growth factors
- Total bilirubin =< 1.5 x upper limit of normal (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)
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) <
2.5 x institutional upper limit of normal
- Albumin > 3 g/dL
- Estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m^2; per Modification of
Diet in Renal Disease (MDRD) calculation or institutional standard
- Potassium >= 3.5 mmol/L
- Medications known to lower the seizure threshold must be discontinued or substituted
at least 4 weeks prior to day 1 of study
- 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
- Ability to understand, and the willingness to sign, a written informed consent
document, as well as comply with study requirements
Exclusion Criteria:
- Subjects who are unwilling to stop taking saw palmetto, PC-SPECs or other herbal
agents known to affect the PSA
- Patients may not have received any other investigational agents within 30 days prior
to day 1 of study
- Prior exposure to apalutamide, enzalutamide, abiraterone acetate, darolutamide, or any
other second-generation antiandrogen therapy
- Note: prior exposure to bicalutamide, flutamide, nilutamide, or any other
first-generation androgen receptor antagonist is permitted. No washout is
required. Subjects may be on one of these at the time of consent, but it must be
stopped prior to day 1 of study treatment. These drugs are frequently used in the
newly diagnosed metastatic setting to blunt the effect of the testosterone spike
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to apalutamide or other agents used in the study
- Subject has another active malignancy other than non-melanomatous skin cancer (unless
it is metastatic) or superficial bladder cancer
- Either of the following:
- Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke
within 1 year, brain arteriovenous malformation, Schwannoma, meningioma, or other
benign central nervous system [CNS] or meningeal disease which may require
treatment with surgery or radiation therapy)
- Severe or unstable angina, myocardial infarction, symptomatic congestive heart
failure or left ventricular ejection fraction < 50%, arterial or venous
thromboembolic events (e.g. pulmonary embolism, cerebrovascular accident
including transient ischemic attacks), or clinically significant ventricular
arrhythmias within 6 months prior to day 1 of study
- Current evidence of any of the following:
- Uncontrolled hypertension
- Gastrointestinal disorder affecting absorption
- Active infection (e.g. human immunodeficiency virus [HIV] or viral hepatitis)
- Any chronic medical condition requiring a higher dose of corticosteroid than a
total of 10 mg prednisone/prednisolone daily
- Any condition that in the opinion of the investigator, would preclude
participation in this study.
- Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment. If
a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate
dosing frequency to twice a day only during the co-administration period (e.g.,
from 1,000 mg once daily to 1,000 mg twice a day).
- Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have a
narrow therapeutic index. If an alternative treatment cannot be used, exercise
caution and consider a dose reduction of the concomitant CYP2D6 substrate
- Baseline moderate and severe hepatic impairment (Child Pugh Class B & C)
- Inability to stop a prohibited medication:
- Atypical antipsychotics (e.g. clozapine, olanzapine, risperidone, ziprasidone)
- Bupropion
- Lithium
- Meperidine and pethidine
- Phenothiazine antipsychotics (e.g. chlorpromazine, mesoridazine, thioridazine)
- Tricyclic antidepressants (e.g. amitriptyline, desipramine, doxepin, imipramine,
maprotiline, mirtazapine
- Tramadol
