Comparing Standard of Care Chemotherapy Treatment to the Combination of Copanlisib and Olaparib for Recurrent Platinum Resistant Ovarian Cancer That Has Progressed Through PARP Inhibitor Therapy

Patients with recurrent ovarian cancer. Ovarian cancer = fallopian tube cancer, ovarian cancer, primary peritoneal cancer. The following histology types are eligible:

* High grade serous

* Endometrioid, grade 3

* Any histology with BRCA1 and/or BRCA2 deleterious mutation (germline or somatic)

* Histologic confirmation of the original primary tumor is required via the pathology report (upload of report required)

* Confirmation of BRCA1 and BRCA2 germline status is required for all entered patients (upload of report\[s\] required)

* Tumor/somatic genomic testing can be provided or entered as not done (upload of report\[s\] required)

* Homologous recombination deficiency (HRD) testing can be provided or entered as not done (upload of report\[s\] required)

* Genetic/genomic testing results and HRD testing results, initially entered as not done, should be uploaded if they become available anytime during conduct of the study

Participants must have progressed by imaging while receiving PARP inhibitor therapy (irrespective of whether PARP inhibitor therapy was given as maintenance therapy or as primary recurrence therapy); rising CA125 only is not considered as evidence of progression

Platinum-resistant disease, defined as progression within \< 6 months from completion of platinum-based therapy, and inclusive of platinum refractory disease. The date should be calculated from the last administered dose of platinum therapy

Unlimited lines of cytotoxic therapy allowed in the platinum-sensitive setting; =\< 2 lines of cytotoxic therapy allowed in the platinum-resistant setting

* Hormonal therapy (e.g., tamoxifen, aromatase inhibitors) will not count as a previous line of therapy

Prior use of bevacizumab in the upfront or recurrent setting is required

Participants must have evaluable disease - defined as RECIST 1.1 measurable disease OR non-measurable disease (defined as solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions OR ascites and/or pleural effusion that has been pathologically demonstrated to be disease-related in the setting of a CA125 \> 2 x upper limit of normal \[ULN\])

Age \>= 18

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 or 2

Absolute neutrophil count (ANC) \>= 1,500/mcl (within 14 days prior to registration)

Hemoglobin \>= 10 g/dL (within 14 days prior to registration)

Platelets \>= 100,000/mcL (within 14 days prior to registration)

Creatinine clearance (CrCL) \>= 51 mL/min (estimated using Cockcroft-Gault equation) (within 14 days prior to registration)

Total serum bilirubin level =\< 1.5 x ULN (patients with known Gilbert's disease who have bilirubin level =\< 3 x ULN may be enrolled) (within 14 days prior to registration)

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3 x ULN (within 14 days prior to registration)

Lipase =\< 1.5 x ULN within 14 days of registration

International normalized ratio (INR) =\< 1.5 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) =\< 1.5 times the upper limit of normal within 14 days of registration

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional classification. To be eligible for this trial, patients should be class 2B or better

Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT is stable. Oral anticoagulants are allowed provided there are no interactions

The effects of copanlisib and olaparib on the developing human fetus are unknown. For this reason and because maternal toxicity, developmental toxicity and teratogenic effects have been observed in nonclinical studies and PI3K inhibitors agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 1 month after the last dose of copanlisib and/or olaparib. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial

Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated

The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

* Known psychiatric illness/social situations that would limit compliance with study requirements.

* History of or current autoimmune disease

* Non-healing wound, ulcer, or bone fracture

* Active, clinically serious infections \> grade 2 (CTCAE v5.0)

Women who are pregnant or unwilling to discontinue nursing

Patients who have a history of non-infectious pneumonitis/interstitial lung disease (ILD) that required steroids, or current non-infectious pneumonitis/ILD

What this study is about