Saruparib in HRDsig+ Solid Tumors

Inclusion Criteria: * Eastern Cooperative Oncology (ECOG) performance status of 0 to 1 * Diagnosis of a metastatic or locally advanced solid tumor malignancy for which no cure is considered possible. 1. Patients with breast, ovarian, prostate or pancreatic cancer may not enroll within Cohort A 2. Patients with ovarian cancer may not enroll in Cohort B * No history of resistance to platinum therapy, defined as disease progression within six months of exposure to platinum chemotherapy (ie cisplatin, oxaliplatin, carboplatin). Patients may be platinum-naïve at time of enrollment. * Progressing at time of enrollment * Measurable disease * Tumor is HRDsig+ by Foundation Medicine Inc assay a. Patients in Cohort A must also have a documented pathogenic germline or somatic variant in BRCA1, BRCA2, PALB2, RAD51B, RAD51C, RAD51D or BARD1 as assessed by a CLIA certified laboratory (this can be done at any time prior to enrollment via tissue assay). Central review of variants must be performed by PI prior to patient enrollment. * Adequate organ function confirmed by the following laboratory values obtained during the screening period: 1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 2. Platelets ≥ 100 x 109/L 3. Hemoglobin ≥ 10g/dL 4. ALT and AST ≤2.5×ULN; for participants with hepatic metastases, ALT and AST ≤5×ULN 5. Total bilirubin ≤ 1.5x ULN. If liver metastases or metabolic disorder such as Gilbert's Syndrome, then ≤2.5x ULN 6. eGFR of ≥ 45 mL/min/1.73m2 as determined by CKD-EPI formula (Inker et al 2021). * For male participants with SCr ≤ 0.9 mg/dL, use the following formula: 142 x (SCr/0.9)-0.302 x 0.9938Age (years) * For male participants with SCr \> 0.9 mg/dL, use the following formula: 142 x (SCr/0.9)-1.200 x 0. 9938Age (years) * For female participants with SCr \< 0.7 mg/dL, use the following formula: 142 x (SCr/0.7)-0.241 x 0.9938Age (years) x 1.012 * For female participants with SCr \> 0.7 mg/dL, use the following formula: 142 x (SCr/0.7)-1.200 x 0.9938Age (years) x 1.012 Exclusion Criteria: * Reversion variant in the peripheral blood as assessed by a CLIA certified local assay (Cohort A only) * Prior exposure to PARP inhibition * Evidence of platinum-resistance, defined as disease progression within six months of exposure to a platinum chemotherapy (ie cisplatin, oxaliplatin, carboplatin) * Clinical evidence of uncontrolled malabsorption and/or any other gastrointestinal disorder or defect that would in the opinion of the investigator, interfere with absorption of saruparib * Acute infection requiring intravenous antibiotics, antiviral or antifungal agents during the 7 days prior to first dose of saruparib * Participants with INR \>2 or higher * Evidence of active and uncontrolled hepatitis B and/or hepatitis C. Screening for hepatitis B and hepatitis C is not required. Participants previously exposed to hepatitis B or hepatitis C are eligible if they meet one of the following criteria: a. Are negative for HBsAg and anti-HBc; or b. Are HBsAg+ and anti-HBc+ (chronic hepatitis B), and meet conditions i to iii below: i. HBV DNA viral load \< 2000 IU/mL. ii. Have normal aminotransferase values. iii. Start antiviral treatment at least 2 weeks prior to the first dose of study intervention and maintain antiviral treatment during the interventional period. c. Are anti-HBc positive, HBsAg negative, and have HBV DNA \< 2000 IU/mL. d. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. * Evidence of active and uncontrolled HIV infection. Participants with controlled HIV need to meet the following criteria: undetectable viral RNA load less than 400 copies/mL in the last 4 weeks prior to first dose of study intervention, CD4+ count of ≥ 350 cells/μL, no history of AIDS-defining opportunistic infection within the past 12 months, and stable on the same anti-HIV medications. Screening for HIV is not required. * Symptomatic or untreated CNS metastases. 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. Corticosteroid dose should not exceed 10mg/day of prednisone or its equivalent * Expected life expectancy of \<12 weeks as determined by the investigator * For fertile patient (female patient able to become pregnant or male able to father a child), refusal to use effective contraception during the period of the trial * Received any systemic treatment for their advanced malignancy 3 weeks prior to first dose of saruparib * Active drug or alcohol use or dependence that would interfere with study adherence * Presence of any other condition that may increase the risk associated with study participation or may interfere with interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for entry into the study. * Participant meets one or more of the following: * Mean resting corrected QT interval \>470 ms, obtained from triplicate ECGs performed at screening. * History of QT prolongation associated with other medications that required discontinuation of that medication. * Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. * History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the Investigator judgement with cardiologist consultation recommended. * Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period prior to starting study treatment is 2 weeks. * Concomitant use of known strong CYP3A4 inducers (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. * Other malignancy unless curatively treated with no evidence of disease for ≥2 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma. Patients with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease * Persistent toxicities (\>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia and grade 2 prior platinum-therapy-related neuropathy. * Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML. * History of persisting (\> 2 weeks) severe pancytopenia due to any cause (eg, ANC \< 0.5 x 109 /L or platelets \< 50 x 109 /L) * As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases including but not limited to uncontrolled hypertension, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, renal transplant, active bleeding diseases, superior vena cava syndrome, extensive interstitial bilateral lung disease which, in the investigator's opinion, makes it undesirable for the subject to participate in the study or that would jeopardise compliance with the protocol. * Major surgery (excluding local surgery of isolated lesions for palliative treatment or diagnostic staging) within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery or an anticipated need for major surgery during the study. * Participation in another clinical study with exposure to an investigational product within 30 days or five half-lives (whichever is the longer) prior to initiating study treatment * Patients with a known hypersensitivity to saruparib or any of the excipients of the product.