This phase II trial studies how well testosterone (enanthate or cypionate) and olaparib work
in treating patients with prostate cancer that has progressed despite hormonal therapy.
Hormonal therapy, such as leuprolide, may lessen the amount of male sex hormones made by the
body. In patients that have developed progressive cancer in spite of standard hormonal
treatment (i.e. castration-resistant prostate cancer), administering testosterone may result
in regression of tumors by causing DNA damage in cancer cells that have adapted to low
testosterone conditions. Olaparib may stop the growth of tumor cells by blocking some of the
enzymes involved in repairing DNA damage. Therefore, giving testosterone and olaparib
together may work better in treating castration-resistant prostate cancer by generating DNA
damage that the cancer cell is unable to repair.
Inclusion Criteria:
- Must be willing to provide informed consent prior to any study specific procedures
- Documented histologically confirmed adenocarcinoma of the prostate
- Patient must have evidence of castration resistant prostate cancer as evidenced by PSA
progression (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a castrate
serum testosterone level (i.e., ≤ 50 mg/dL)
- PSA must be at least 1 ng/ml and rising on two successive measurements at least two
weeks apart
- Patients must have progressed on abiraterone and/or enzalutamide; there must be at
least a 3-week washout period after stopping the most recent approved therapy for
mCRPC (i.e., abiraterone, enzalutamide, Ra-223, sipuleucel-t); if applicable, patients
should be weaned off steroids at least 1 week prior to starting treatment
- No prior chemotherapy for the treatment of mCRPC; patients may have received docetaxel
for the treatment of hormone-sensitive prostate cancer
- Prior treatment with non-chemotherapy investigational agents is permitted; there must
be at least a 3-week washout period after stopping any investigational cancer agent
- Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days
prior to administration of study treatment)
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (within 28 days prior to administration
of study treatment)
- Platelet count ≥ 100 x 10^9/L (within 28 days prior to administration of study
treatment)
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (within 28 days
prior to administration of study treatment)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤
2.5 x institutional upper limit of normal unless liver metastases are present in which
case they must be ≤ 5 x ULN (within 28 days prior to administration of study
treatment)
- Patients must have creatinine clearance estimated using the Cockcroft-Gault equation
or based on a 24 hour urine test of ≥ 51 mL/min (within 28 days prior to
administration of study treatment)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Patients must have a life expectancy ≥ 16 weeks
- Male patients and their partners, who are sexually active and of childbearing
potential, must agree to the use of two highly effective forms of contraception in
combination throughout the period of taking study treatment and for 3 months after
last dose of study drug(s) to prevent pregnancy in a partner
- Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations
- At least one lesion (measurable and/or non-measurable) that can be accurately assessed
at baseline by computed tomography (CT), positron-emission tomography (PET), magnetic
resonance imaging (MRI) and/or bone scan and is suitable for repeated assessment
- Must have archival tissue available, be willing to undergo metastatic biopsy or have a
sufficient plasma circulating tumor DNA (ctDNA) concentration in order to perform
next-generation DNA sequencing
- The study will require that 50% of enrolled subjects have homozygous deletions,
deleterious mutations, or both in one or more of the DNA damage response (DDR) genes;
the other 50% of patients must have an intact DDR pathway
Exclusion Criteria:
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
- Previous enrollment in this study
- Participation in another clinical study with an investigational product during the
last 3 weeks
- Any previous treatment with poly-adenosine diphosphate ribose polymerase (PARP)
inhibitor, including olaparib
- Other malignancy unless curatively treated with no evidence of disease for ≥ 5 years
except: adequately treated non-melanoma skin cancer
- Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
cardiac conditions, as judged by the investigator (e.g. unstable ischemia,
uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's corrected
QT interval [QTcF] prolongation > 500 ms, electrolyte disturbances, etc.), or patients
with congenital long QT syndrome
- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment
- Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout
period prior to starting olaparib is 2 weeks
- Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or
moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil); the required washout
period prior to starting olaparib is 3 weeks for enzalutamide, 5 weeks for
phenobarbital and 3 weeks for other agents
- Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade
2) caused by previous cancer therapy, excluding alopecia
- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
- Patients with symptomatic uncontrolled brain metastases; a scan to confirm the absence
of brain metastases is not required; the patient can receive a stable dose of
corticosteroids before and during the study as long as these were started at least 4
weeks prior to treatment; patients with spinal cord compression unless considered to
have received definitive treatment for this and evidence of clinically stable disease
for 28 days
- Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery
- Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection; examples
include, but are not limited to, uncontrolled ventricular arrhythmia, history of prior
myocardial infarction, uncontrolled major seizure disorder, uncontrolled hypertension
(blood pressure [BP] ≥ 160/100), history of prior stroke, uncontrolled diabetes
(glycosylated hemoglobin [hgb A1C] > 7), unstable spinal cord compression, superior
vena cava syndrome, extensive interstitial bilateral lung disease on high resolution
computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining
informed consent
- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication
- Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV)
- Patients with a known hypersensitivity to olaparib or any of the excipients of the
product
- Patients with a known hypersensitivity to the testosterone cypionate or any of the
excipients of the product
- Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of
transmitting the infection through blood or other body fluids
- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable)
- Evidence of serious and/or unstable pre-existing medical, psychiatric or other
condition (including laboratory abnormalities) that could interfere with patient
safety or provision of informed consent to participate in this study
- Any psychological, familial, sociological, or geographical condition that could
potentially interfere with compliance with the study protocol and follow-up schedule
- Evidence of disease that, in the opinion of the investigator, would put the patient at
risk from testosterone therapy (e.g. femoral metastases with concern over fracture
risk, spinal metastases with concern over spinal cord compression, lymph node disease
with concern for ureteral obstruction)
- Patients with pain attributable to their prostate cancer
- Tumor causing urinary outlet obstruction that requires catheterization for voiding;
patients that require catheterization to void secondary to benign strictures or other
non-cancer causes will be permitted to enroll
- Prior history of deep venous thrombosis or pulmonary embolism within 5 years prior to
enrollment in the study and not currently on systemic anticoagulation
- Patients with NYHA (New York Heart Association) class III or IV heart failure or
history of a prior myocardial infarction (MI) prior to enrollment in the study
