Abiraterone Acetate and Prednisone With or Without Veliparib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To evaluate the role of v-ets erythroblastosis virus E26 oncogene (ETS) gene fusion as a
predictive biomarker for response to hormone therapy (abiraterone [abiraterone acetate])
alone or hormone therapy plus poly adenosine diphosphate-ribose polymerase 1 (PARP-1)
targeted therapy (ABT-888 [veliparib]) in patients with metastatic castration resistant
prostate cancer.

II. To evaluate whether the addition of PARP-1 targeted therapy is superior to hormone
therapy alone based on ETS gene fusion status.

SECONDARY OBJECTIVES:

I. Rate of prostate-specific antigen (PSA) declines. II. Objective response rate. III.
Progression-free survival. IV. Evaluate the qualitative and quantitative toxicity of
abiraterone acetate with and without ABT-888.

TERTIARY OBJECTIVES:

I. To determine the concordance in fusion status among prostate cancer samples from the
primary site, biopsied metastasis, and circulating tumor cells (CTCs).

II. To assess if ETS fusion status in the CTCs, at baseline, 12 weeks, and disease
progression (or when off study) is associated with response to therapy.

III. To evaluate if the number of CTCs, as well as the expression levels of androgen
receptor, RAD51 recombinase (RAD51), and gamma-H2A histone family, member X (H2aX) foci in
the CTCs at baseline, at 12 weeks, and at disease progression in all patients is associated
with response to therapy.

IV. To determine the role of phosphatase and tensin homolog (PTEN) loss as a predictive
biomarker of response to abiraterone, alone or in combination with ABT-888.

V. To determine the role of PARP1 activity as a predictive biomarker of response to
abiraterone, alone or in combination with ABT-888.

VI. To perform next-generation sequencing for discovery of novel gene fusions in prostate
cancers negative for ETS fusions.

VII. To perform germline single nucleotide polymorphism (SNP) analysis of genes involved in
hormone synthesis, transport, binding, metabolism, and degradation for discovery of novel
SNPs predictive of response to abiraterone, alone or in combination with ABT-888.

VIII. To determine if ETS fusion ribonucleic acid (RNA) levels in blood are predictive of
response to abiraterone, alone or in combination with ABT-888.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive abiraterone acetate orally (PO) once daily (QD) and prednisone PO
twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive veliparib PO BID on days 1-28. Patients also receive abiraterone
acetate PO QD and prednisone PO BID on day 1 (day 8 of course 1). Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 2
years.

Inclusion Criteria:

- Have a histologic or cytologic diagnosis of prostate cancer

- Have progressive metastatic castration-resistant prostate cancer, on
androgen-deprivation therapy, based on at least one of the following criteria:

- PSA progression defined as 25% increase over baseline value with an increase in
the absolute value of at least 2 ng/mL that is confirmed by another PSA level
with a minimum of a 1-week interval with a minimum PSA of 2 ng/mL

- Progression of bidimensionally measurable soft tissue (nodal metastasis) assessed
within one month prior to registration by a computed tomography (CT) scan or
magnetic resonance imaging (MRI) of the abdomen and pelvis

- Progression of bone disease (evaluable disease) (new bone lesion[s]) by bone scan

- Agree to undergo a biopsy of at least 1 metastatic site for gene-fusion status
analysis; adequate archival metastatic tissue can be used if available in lieu of a
biopsy; patients will only be eligible for protocol therapy if the biopsy has tumor
and the tissue is evaluable for ETS fusion status

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Have testosterone < 50 ng/dL; patients must continue primary androgen-deprivation with
a luteinizing hormone-releasing hormone (LHRH) analogue if they have not undergone
orchiectomy

- Patients must discontinue antiandrogen therapy for at least 4 weeks (e.g. flutamide,
bicalutamide, nilutamide) prior to registration with no evidence of a falling PSA
after washout; patients on steroids are eligible as long as they will be switched to
prednisone

- Have no prior exposure to cytochrome 450 family 17(CYP-17) (other than ketoconazole)
or PARP inhibitors for prostate cancer; patients with prior exposure to ketoconazole
are eligible

- Patients with up to 2 prior chemotherapy regimens are eligible

- Obtained within 14 days prior to registration: White blood cells (WBC) >= 3,000/ul

- Obtained within 14 days prior to registration: Absolute neutrophil count (ANC) >=
1,500/ul

- Obtained within 14 days prior to registration: Platelet count >= 100,000/ul

- Obtained within 14 days prior to registration: Serum creatinine =< 1.5 x the
institutional upper limits of normal or corrected creatinine clearance of >= 50
mg/ml/hr/1.73 m^2 body surface area (BSA)

- Obtained within 14 days prior to registration: Potassium >= 3.5 mmol/L

- Obtained within 14 days prior to registration: Bilirubin within the institutional
limits of normal

- Obtained within 14 days prior to registration: Serum glutamic oxaloacetic transaminase
(SGOT) (aspartate aminotransferase [AST]) =< 2 times upper limit of normal

- Obtained within 14 days prior to registration: Serum glutamate pyruvate transaminase
(SGPT) (alanine aminotransferase [ALT]) =< 2 times upper limit of normal

- Measured within 28 days prior to administration of ABT-888: >= 10.0 g/dL hemoglobin
(Hb) with no blood transfusion in the past 28 days

- Men must agree to use effective contraception during treatment and for at least 1 week
after the last administration of therapy

- Patients must be able to take oral medication without crushing, dissolving, or chewing
tablets

- Patients may have received prior radiation therapy or surgery; however, at least 21
days must have elapsed since completion of radiation therapy or surgery and patient
must have recovered from all side effects at the time of registration

- Ability to understand and the willingness to sign a written informed-consent document
that is approved by the local institutional review board

Exclusion Criteria:

- Patients may not be receiving any other investigational agents; any prior
investigational products must be stopped at least 14 days (2-week washout) prior to
registration

- Patients who have had chemotherapy, radiotherapy or oral antifungal agents
(ketoconazole, itraconazole, fluconazole) within 3 weeks prior to entering the study
or those who have not recovered (e.g. back to baseline or grade 1) from adverse events
due to agents administered more than 3 weeks earlier

- There is a potential drug interaction when abiraterone is concomitantly used with
a cytochrome P450 family 2, subfamily D, polypeptide 6 (CYP2D6) substrate narrow
therapeutic index (e.g., thioridazine, dextromethorphan), or strong cytochrome
P450 family 3, subfamily A, polypeptide 4 [CYP3A4] inhibitors (e.g., atazanavir,
erythromycin, indinavir, itraconazole, Ketoconazole, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin, and voriconazole) or strong inducers (e.g.,
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine);
caution should be used when patients are on one of these drugs

- Patients with history of active seizures are not eligible

- Patients with a history of pituitary or adrenal dysfunction, active or symptomatic
viral hepatitis, or chronic liver disease are not eligible

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ABT-888 or abiraterone

- Patients may continue on a daily multi-vitamin, calcium and vitamin D, but all other
herbal, alternative and food supplements (i.e. PC-Spes, saw palmetto, St John's wort,
etc.) must be discontinued before registration; patients must not be planning to
receive any concurrent cytotoxic chemotherapy, surgery, or radiation therapy during
protocol treatment; hormonal-acting agents (including diethylstilbestrol/DES,
aldosterone, and spironolactone) are forbidden during the trial and must be stopped
prior to registration; no washout period will be required for any of these agents;
patients on megestrol acetate for hot flashes are allowed to continue therapy

- Patients on stable doses of bisphosphonates or denosumab which have been started prior
to registration may continue on this medication, patients who are not on
bisphosphonates or denosumab are eligible as long as they initiate therapy prior to
registration

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (New York Heart Association class III
and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements or
concurrent medications that alter cardiac conduction

- Patients with a "currently active" second malignancy other than non-melanoma skin
cancers are not eligible; patients are not considered to have a "currently active"
malignancy if they have completed all therapy and are now considered without evidence
of disease for 1 year

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic
syndrome (MDS) or with features suggestive of AML/MDS. Prior allogeneic bone marrow
transplant or double umbilical cord blood transplantation