Olaparib With or Without Atezolizumab in Treating Patients With Locally Advanced or Metastatic Non-HER2-Positive Breast Cancer

PRIMARY OBJECTIVES:

I. To compare the progression free survival (PFS) between two study arms, i.e., olaparib
monotherapy (arm 1) and olaparib + atezolizumab in combination (arm 2) based on normal
Response Evaluation Criteria in Solid Tumors (RECIST) criteria in patients with locally
advanced or metastatic non-HER2-positive breast cancer harboring homologous deoxyribonucleic
acid (DNA) repair (HDR) through BRCA 1/2 mutation.

SECONDARY OBJECTIVES:

I. To compare the progression free survival (PFS) between the two study arms based on immune
response criteria.

II. To compare the time to treatment failure (TTF) between the two study arms based on immune
response criteria and normal RECIST.

III. To compare the overall response rate (ORR) between the two study arms based on immune
response criteria and normal RECIST.

IV. To compare the duration of response (DoR) between the two study arms based on immune
response criteria and normal RECIST.

V. Determine the changes in extent of mutational burden in BRCA 1/2 mutated tumors at
baseline and at progression.

VI. Evaluate and characterize changes in the extent of PD-L1 expression and tumor immune
infiltrates.

VII. Retrospectively evaluate tumors with limited immune infiltrate (e.g. "non-inflamed") to
determine if PARPi increased immune infiltration.

VIII. Determine the immune-related best overall response (irBOR) of olaparib in combination
with atezolizumab in locally advanced or metastatic non-HER2+ breast cancer harboring HDR
through BRCA 1/2 mutation.

TERTIARY OBJECTIVES:

I. Evaluate changes in candidate neoantigen profiles and immune/inflammation signatures using
DNA and ribonucleic acid (RNA)-sequencing in serial tumor biopsies.

II. Evaluate and characterize circulating tumor DNA (ctDNA) and immune parameters in blood.

III. Test the hypothesis that DNA repair status affects the tumor-immune interaction.

IV. Characterize mechanism of action of the PARP inhibitor olaparib. V. To explore the
inclusion of patient reported symptomatic adverse events. VI. To use anti-Kynurenine
antibodies for immunohistochemistry (IHC) as well as unbiased metabolome studies on plasma to
understand the metabolic consequences of PARP-inhibition and their effects on immune
infiltrates.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive olaparib orally (PO) twice daily (BID) on days 1-21. Cycles repeat
every 21 days in the absence of disease progression or unacceptable toxicity. Patients with
disease progression may cross-over to Arm II.

ARM II: Patients receive olaparib as Arm I and atezolizumab intravenously (IV) over 30-60
minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up monthly.

Inclusion Criteria:

- Patients must have histologically documented unresectable locally advanced or
metastatic non-HER2-positive breast cancer and a known BRCA 1/2 mutation present

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
imaging (MRI), or calipers by clinical exam

- Prior chemotherapy is allowed, including platinum therapy; patients must not have
received chemotherapy for 4 weeks prior to the initiation of study treatment and must
have recovery =< grade 1 from any adverse events from any prior chemotherapy (other
than alopecia); patients must not have had nitrosoureas or mitomycin C for 6 weeks
prior to the initiation of study treatment

- Prior radiation therapy is allowed; patients must not have received minimal radiation
therapy (=< 5% of their total marrow volume) within 3 weeks prior to the initiation of
study treatment; otherwise, patients must not have received radiation therapy (> 5% of
their total marrow volume) within 4 weeks prior to the initiation of study treatment;
patients who have received prior radiation to 50% or more of their total marrow volume
will be excluded

- Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided
the following requirements are met: minimum of 12 weeks from the first dose of
anti-CTLA-4 and > 6 weeks from the last dose, and no history of severe immune-related
adverse effects from anti-CTLA-4 (National Cancer Institute [NCI] Common Terminology
Criteria for Adverse Events [CTCAE] grade 3 and 4)

- Treatment with systemic immunosuppressive medications (including, but not limited to,
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) is allowed, provided the following is met: minimum
of 2 weeks prior to cycle 1, day 1; patients who have received acute, low dose,
systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for
nausea) may be enrolled; the use of corticosteroids and mineralocorticoids (e.g.,
fludrocortisone) for patients with orthostatic hypotension or adrenocortical
insufficiency is allowed

- Prior treatment with systemic immunostimulatory agents (including, but not limited to,
interferon [IFN]-alpha or interleukin [IL]-2) is allowed, provided the following is
met: minimum of 6 weeks prior to cycle 1, day 1

- Patients taking bisphosphonate therapy for symptomatic hypercalcemia are NOT allowed;
use of bisphosphonate therapy for other reasons (e.g., bone metastasis or
osteoporosis) is allowed

- Prior hormone therapy is allowed; patients must not have received hormone therapy for
breast cancer for 2 weeks prior to the initiation of study treatment and must have
recovery =< grade 1 from any adverse events related to these therapies (other than
alopecia)

- Prior experimental (non-Food and Drug Administration [FDA] approved) therapies and
immunotherapies are allowed; patients must not have received these therapies for 4
weeks prior to the initiation of study treatment and must have recovery =< grade 1
from any adverse events of these therapies (other than alopecia); prior treatment with
any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibody is NOT allowed

- Other therapies (e.g. targeted therapy such as cyclin-dependent kinase [CDK]
inhibitors): patients should have recovered to =< grade 1 drug related toxicity; they
must have completed therapy for either a total of duration equivalent to 5 half-lives
of the drug or 28 days, whichever is shorter

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 6 months

- Absolute neutrophil count >= 1,500/mcL

- Leukocytes >= 3,000/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 8 g/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (however, patients with known
Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
2.5 x upper limit of normal (ULN) if no liver metastasis; =< 5 x upper ULN if liver
metastasis present

- Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver
involvement or bone metastases)

- Creatinine clearance >= 51 mL/min/1.73 m^2 by Cockcroft-Gault

- International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
=< 1.5 x ULN (this applies only to patients who do not receive therapeutic
anticoagulation; patients receiving therapeutic anticoagulation, such as
low-molecular-weight heparin or warfarin, should be on a stable dose)

- No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
on peripheral blood smear

- Patients must have tumors determined to be easily accessible for biopsy and must be
willing to have serial biopsies (with a third biopsy upon evidence of disease
progression)

- Administration of atezolizumab and/or olaparib may have an adverse effect on pregnancy
and poses a risk to the human fetus, including embryo-lethality; women of
child-bearing potential and men must agree to use highly effective contraception prior
to study entry, for the duration of study participation, and for at least 5 months
(150 days) after the last dose of study agent; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately; men treated or enrolled on this
protocol must also agree to use two highly effective forms of contraception in
combination prior to the study, for the duration of study participation, and for at
least 5 months (150 days) after completion of atezolizumab and/or olaparib
administration; women of child-bearing potential: negative serum pregnancy test within
28 days of study treatment and confirmed prior to treatment on day 1; postmenopausal
or evidence of non-childbearing status for women of childbearing potential;
postmenopausal is defined as:

- Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments

- Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
post-menopausal range for women under 50

- Radiation-induced oophorectomy with last menses > 1 year ago

- Chemotherapy-induced menopause with > 1 year interval since last menses

- Surgical sterilization (bilateral oophorectomy or hysterectomy)

- Ability to understand and the willingness to sign a written informed consent document

- Subject is able to swallow and retain oral medication and does not have uncontrolled
emesis or gastrointestinal disorders likely to interfere with absorption of the study
medication

- Patients crossing over from monotherapy to combination therapy do not have to be fully
rescreened; however, they do need to meet performance status, organ function, and
blood parameters and not meet any of the exclusion criteria

- Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this
study, but HIV-positive patients must have:

- A stable regimen of highly active anti-retroviral therapy (HAART)

- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections

- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
polymerase chain reaction (PCR)-based test

Exclusion Criteria:

- Patients with prior allogeneic bone marrow transplantation, double umbilical cord
blood transplantation (dUCBT) or prior solid organ transplantation

- Patients with known brain metastases should be excluded from this clinical trial
except as those described below, because of their poor prognosis and because they
often develop progressive neurologic dysfunction that would confound the evaluation of
neurologic and other adverse events

- Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS
metastases are excluded, with the following exceptions:

- Patients with asymptomatic untreated CNS disease may be enrolled, provided all of
the following criteria are met:

- Evaluable or measurable disease outside the CNS

- No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within
10 mm of the optic apparatus (optic nerves and chiasm)

- No history of intracranial hemorrhage or spinal cord hemorrhage

- No ongoing requirement for dexamethasone for CNS disease; patients on a
stable dose of anticonvulsants are permitted

- No neurosurgical resection or brain biopsy within 28 days prior to cycle 1,
day 1

- Patients with asymptomatic treated CNS metastases may be enrolled, provided all
the criteria listed above are met as well as the following:

- Radiographic demonstration of improvement upon the completion of CNS
directed therapy and no evidence of interim progression between the
completion of CNS directed therapy and the screening radiographic study

- No stereotactic radiation or whole-brain radiation within 28 days prior to
cycle 1, day 1

- Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
and >= 2 weeks from discontinuation of corticosteroids

- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to olaparib and atezolizumab; patients with a known hypersensitivity to
olaparib or any of the excipients of the product

- Prior treatment with any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibody

- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease

- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible

- Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR
is negative for HCV RNA

- History or risk of autoimmune disease, including, but not limited to, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, lichen sclerosis, or glomerulonephritis

- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible

- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible

- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:

- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations

- Rash must cover less than 10% of body surface area (BSA)

- Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

- No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids)

- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan; history of radiation pneumonitis in the radiation field
(fibrosis) is permitted if recovered

- Major surgical procedure within 28 days prior to cycle 1, day 1 and patients must have
recovered from any effects of any major surgery; anticipation of need for a major
surgical procedure during the course of the study

- Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
anticipation that such a live, attenuated vaccine will be required during the study
and up to 5 months after the last dose of atezolizumab

- Influenza vaccination should be given during influenza season only (approximately
October to March); patients must not receive live, attenuated influenza vaccine
within 4 weeks prior to cycle 1, day 1 or at any time during the study

- 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, recent (within 3
months) myocardial infarction, unstable spinal cord compression, superior vena cava
syndrome, symptomatic congestive heart failure, unstable angina pectoris, extensive
interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan
or any psychiatric disorder that prohibits obtaining informed consent and would limit
compliance with study requirements

- Pregnant women are excluded from this study because olaparib and atezolizumab are have
the potential for teratogenic or abortifacient effects; because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of the
mother with olaparib and atezolizumab, breastfeeding should be discontinued if the
mother is treated with olaparib and atezolizumab

- Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE > grade 1

- Patients with active seizures or a history of uncontrolled seizure disorder, including
focal or generalized seizure within the past year

- Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot
discontinue it before treatment with atezolizumab

- Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec or family history
of long QT syndrome

- Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout
per