Study Groups:
If you are found to be eligible to take part in this study, you will be randomly assigned (as
in a roll of dice) to 1 of 2 study groups. This is done because no one knows if one study
group is better, the same, or worse than the other group. You will have a 2 in 3 chance of
being assigned to Group 1 and a 1 in 3 chance of being assigned to Group 2:
- If you are in Group 1, you will receive olaparib.
- If you are in Group 2, you will not receive olaparib.
All participants will receive cabazitaxel and carboplatin.
You and the study staff will know to which group you have been assigned.
Study Drug Administration:
Each study cycle is 21 days.
You will receive cabazitaxel by vein over 60 minutes on Day 1 of Cycles 1-6. You will then
receive carboplatin by vein over 60 minutes on Day 1 of Cycles 1-6.
You will take 1 tablet of prednisone by mouth 2 times each day of Cycles 1-6.
You will be given standard drugs to help decrease the risk of side effects (for example,
filgrastim) before and/or after each dose of cabazitaxel and continuing through several days.
Your doctor will describe these drugs to you in more detail, including how they are given and
any side effects you may expect.
If you are in Group 1, you will take tablets of olaparib 2 times by mouth each day starting
on Day 1 of Cycle 7. Swallow the whole tablet or tablets. Do not chew, crush, divide, or
dissolve the tablets. If you vomit shortly after taking your olaparib tablet you can retake a
new dose as long as you can see that the tablet came out whole. You should take the doses at
the same time each day (or within 2 hours of the scheduled times). Do not take the dose if
you forget and it is more than 2 hours since your scheduled time. Take olaparib at least 1
hour after and 2 hours before eating.
If you are in Group 2, you will receive standard of care treatment and follow-up after Cycle
6. The study doctor will tell you more about what this may mean for you.
Length of Treatment:
You will receive carboplatin and cabazitaxel for up to 6 cycles. If you are in Group 1, you
may continue receiving olaparib for as long as the doctor thinks it is in your best interest.
You may no longer be able to take the study drugs if the disease gets worse, if intolerable
side effects occur, or if you are unable to follow study directions.
Your participation on the study will be over after the follow-up visits.
Study Visits:
On Day 1 of Cycles 1-6:
- You will have a physical exam.
- Blood (up to 5 tablespoons) will be drawn for routine tests, biomarker testing, tumor
marker testing, and to measure your PSA level. At some of these visits, this sample will
also be used for CTC testing. You must fast for up to 12 hours before the Cycle 4 visit.
- Urine will be collected for tumor marker testing.
- At Cycle 4 only, you will have a bone scan and either MRIs or CT scans to check the
status of the disease.
After Cycle 6, you will have a second tumor biopsy for biomarker testing to compare to the
one taken at screening. The type of biopsy you have will depend on where the disease has
spread and/or what the doctor thinks is in your best interest. The doctor will discuss with
you the type of biopsy you will have.
On Day 1 of Cycle 7:
- Blood (up to 5 tablespoons) will be drawn to check your testosterone levels, biomarker
testing, and for tumor marker testing.
- You will have an EKG.
- You will have a bone scan and either MRIs or CT scans.
On Day 1 of Cycles 8-10:
- You will have a physical exam.
- Blood (up to 5 tablespoons) will be drawn for routine tests, tumor marker testing,
biomarker testing, and to measure your PSA level. At some of these visits, this sample
will also be used for CTC testing.
- Urine will be collected for tumor marker testing.
After Cycle 10, you will only have study visits every 3 cycles. Beginning on Day 1 of Cycle
13, every 3 cycles (Cycles 13, 16, 19, and so on):
- You will have a physical exam.
- Blood (up to 5 tablespoons) will be drawn for routine tests, tumor marker testing,
biomarker testing, and to measure your PSA level. At some of these visits, this sample
will also be used for CTC testing. You must fast for up to 12 hours before the visits at
Cycle 10 and every 3 cycles after that.
- Urine will be collected for tumor marker testing.
- You will have a bone scan and either MRIs or CT scans to check the status of the
disease.
- You will have an EKG.
If you have severe side effects, you may return to the clinic more often so the study doctor
can check on your health.
End of Study Visit:
When you leave the study, the following tests and procedures will be performed:
- You will have a physical exam.
- You will have a bone scan and either MRIs or CT scans to check the status of the
disease.
- You will have an EKG.
- Blood (about 3 tablespoons) will be drawn for routine tests, tumor marker testing, and
to measure your PSA level. You must fast for up to 12 hours before this visit.
- Urine will be collected for tumor marker testing.
Follow-Up:
About every 6 months after the end-of-study visit, the study staff will check your health.
This will be done either by a chart review or a phone call. If you are called, this call will
last about 5 minutes. These calls will stop if you withdraw from the study.
Inclusion Criteria:
1. Provision of informed consent prior to any study specific procedures.
2. Provision of informed consent for genetic research. If a patient declines to
participate in the genetic research, there will be no penalty or loss of benefit to
the patient. The patient will not be excluded from other aspects of the study
described in this Clinical Study Protocol, so long as they consent to that part.
3. Patients must agree to tissue collection for correlative studies at the specified
timepoints. If patient has undergone a recent tissue collection without intervening
treatment since, that can be retrieved and is deemed of sufficient quantity by the PI
to undertake the proposed correlative studies, it may be used as the baseline.
4. Male aged 18 years and above.
5. Histologically or cytologically confirmed prostate carcinoma.
6. Presence of metastatic disease documented on imaging studies (bone scan, computed
tomography (CT) and/or magnetic resonance imaging (MRI) scans).
7. Patients must meet at least one of the following AVPC criteria: i. Histologically
proven small cell (neuroendocrine) prostate carcinoma ii. Exclusive visceral
metastases. iii. Predominantly lytic bone metastases identified by plain x-ray or CT
scan. iv. Bulky (>/= 5cm in longest dimension) lymphadenopathy or high-grade tumor
mass in prostate/pelvis. v. Low PSA (</= 10ng/mL) at initial presentation (prior to
androgen ablation or at symptomatic progression in the castrate-setting) plus high
volume (>/= 20) bone metastases. vi. Elevated serum lactate dehydrogenase (>/=2 x
upper limit of normal) or elevated serumcarcinoembryonic antigen (>/= 2 x upper limit
of normal ) in the absence of other etiologies. vii. Short interval (</= 180 days) to
castrate-resistant progression following initiation of hormonal therapy. viii. Known
loss or mutation (by CLIIA certified molecular testing, IHC and/or DNA sequencing) in
at least 2 of the following: Tp53, RB1 and PTEN.
8. (continued from Inclusion Criteria #7: viiii. Patients who have castration -resistant
disease progression per RECIST but do not meet PCWG3 PSA progression criteria
9. Patients must have documented evidence of progressive disease as defined by any of the
following: a) PSA progression: minimum of 2 rising values (3 measurements) obtained a
minimum of 7 days apart with the last result being at least >/= 1.0 ng/mL; b) New or
increasing non-bone disease (RECIST); c) Positive bone scan with 2 or more new lesions
(PCWG3). d) Increasing symptoms unequivocally attributed to disease progression as
judged by the treating physician and the PI.
10. Surgically or ongoing medically castrated, with baseline testosterone levels of </= 50
ng/dL </= 2.0 nM).
11. Eastern Cooperative Oncology Group (ECOG) Performance Status of </=2.
12. Patients must have normal organ and bone marrow function measured within 7 days prior
to administration of study treatment as defined below: i. Hemoglobin >/= 10.0 g/dL dL
(unless due to bone marrow infiltration by tumor, in which case hemoglobin >/=8gdL is
allowed). Patient may have blood transfusions prior to study enrollment. ii. Absolute
neutrophil count (ANC) >/= 1.5 x 10^9/L (unless due to bone marrow infiltration by
tumor, in which case ANC >1,000/mm3 is allowed) iii. White blood cells (WBC) >3x10^9/L
(unless due to bone marrow infiltration by tumor, in which case WBC >2x109/L is
allowed) iv. No features suggestive of myelodysplastic syndrome/acute myeloid leukemia
on peripheral blood smear v. Platelet count >/= 100 x 10^9/L (unless due to bone
marrow infiltration by tumor, in which case platelet >/=50,000/ mm3 is allowed) vi.
Total bilirubin </=1.5 x institutional upper limit of normal (ULN) (except for
patients with known Gilbert's disease).
13. (continued from Inclusion Criteria #11 vii. aspartate aminotransferase (serum
glutamine oxaloacetic transminase) and alanine aminotransferase (serum glutamic
pyruvic transaminase) </= 2.5 x institutional upper limit of normal (unless liver
metastases are present in which case it must be </= 5x ULN) viii. Calculated
creatinine clearance (Cockcroft-Gault Equation) >/= 40 mL/min.
14. Able to swallow study drugs whole as a tablet/capsule.
15. Patients who have partners of childbearing potential (e.g. female that has not been
surgically sterilized or who are not amenorrheic for >/= 12 months) must be willing to
use a method of birth control in addition to adequate barrier protection as determined
to be acceptable by the investigator during the study and for 13 weeks after last
study drug administration. Please note that the efficacy of hormonal contraception may
be decreased if administered with olaparib.
16. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
Exclusion Criteria:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at MD Anderson)
2. Previous enrolment or randomization in the present study
3. Any prior treatment for castration-resistant prostate cancer (CRPC) with carboplatin,
cisplatin, cabazitaxel or olaparib.
4. Patients whose disease is refractory (defined as evidence of disease progression while
on drug or within 3 months of its discontinuation) to more than 2 lines of
chemotherapy given for CRPC. Any number of chemotherapies to which the patient's
disease is not refractory are allowed, as long as time on treatment did not exceed 6
months (counted from day 1 of cycle 1 to day 1 of the last cycle of treatment).
5. Patients who have not recovered from adverse events secondary to systemic therapy
(except for luteinizing hormone-releasing (LHRH) hormone agonist or antagonist
treatment for prostate cancer, and bisphosphonates or receptor activator of Nf kappa
(RANK) ligand inhibitors for bone strengthening), major surgery or radiotherapy for
the treatment of prostate cancer to a grade </= 2.
6. Persistent toxicities (>/= common terminology criteria for adverse events grade 2)
with the exception of alopecia, caused by previous cancer therapy.
7. Chronic use of known strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole,
ritonavir, indinavir, saquinavir, telithromycin, clarithromycin, voriconazole,
nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir,
boceprevir, telaprevir and nelfinavir), moderate CYP3A4 inhibitors (e.g. amprenavir,
aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem,
erythromycin, fluconazole, fosamprenavir, imatinib, verapamil), strong CYP3A4 inducers
(e.g. phenytoin, rifampicin, carbamazepine, St.John's Wort, phenobarbital) and
moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil and
nafcillin). Concomitant use of these drugs with olaparib is not allowed. Patients may
undergo limited courses of them prior to starting olaparib but will be required to
have >/= 5 week washout period from phenobarbital, and >/=3 week washout period from
the rest, before randomization.
8. Active uncontrolled infection ( patients completing a course of antibiotic or
antiviral therapy whose infection is deemed to be controlled may be allowed on study
after discussion with the PI; the PI will serve as the final arbiter regarding
eligibility).
9. Active or symptomatic viral hepatitis or chronic liver disease.
10. A diagnosis or suspicion of myelodysplastic syndrome/acute myeloid leukemia.
11. A history of pneumonitis or extensive bilateral lung disease of non-malignant
etiology.
12. A malignancy [other than the one treated in this study] which required radiotherapy or
systemic treatment within the past 5 years, or has a >/= 30% probability of recurrence
within 24 months (except for adequately treated non-melanoma skin cancer, curatively
treated in-situ cancer of the Ta urothelial carcinomas).
13. Any underlying medical or psychiatric condition, which in the opinion of the
Investigator, will make the administration of study drug hazardous or obscure the
interpretation of adverse events. Examples include, but are not limited to,
uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction,
superior vena cava syndrome, extensive bilateral lung disease on high-resolution
computed tomography scan, uncontrolled seizures or any psychiatric disorder that
prohibits obtaining informed consent.
14. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
15. Patients with symptomatic uncontrolled brain metastases or spinal cord compressions. 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 28 days prior to treatment.
16. Patients with a known hypersensitivity to the olaparib, carboplatin or cabazitaxel.
17. Prisoners or subjects who are involuntarily incarcerated.
18. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g. infectious disease) illness.
