Immunotherapy Plus Capivasertib for Metastatic Bladder Cancer

Inclusion Criteria: 1. Male or female patients are eligible 2. Diagnosis of urothelial carcinoma, with mixed histology permitted: 1. Histologically or cytologically confirmed advanced or recurrent urothelial carcinoma, OR 2. Documented Stage IV disease (T4b, Any N, M0; any T, Any N, M1a-b), Stage IIIB (T1-T4a, N2-N3, M0), or a subset of Stage IIIA (T1-T4a, N1, M0) 3. Genomic testing, including assessment for PIK3CA, AKT1, or PTEN alterations, must have been performed 4. Patients must have stable disease or cancer progression after at least 12 weeks of Immune Checkpoint Inhibitors (ICI) or ICI-based therapy, per RECIST v1.1 guidelines 5. Patients must have received prior enfortumab vedotin unless contraindicated 6. Patients must be asymptomatic or minimally symptomatic from metastatic urothelial cancer 7. Willingness to receive ICI in combination with capivasertib during the study is required. If cancer progressed on an ICI plus another anti-cancer drug(s) (e.g., pembrolizumab plus enfortumab vedotin), the additional drug(s) must be discontinued for at least 14 days, while ICI is continued, prior to starting capivasertib. 8. Patients must have no or only minimal and stable adverse events from prior cancer-directed therapy, including ICI 9. Measurable disease is required: 1. X-rays, CT/MRI, or physical exams must have been performed within 28 days before starting study medications 2. At least one measurable lesion per RECIST 1.1 must be present at baseline (≥10 mm in longest diameter, or lymph nodes with a short axis ≥15 mm, using CT or MRI; previously irradiated lesions are excluded) 10. Tumor samples: 1. Baseline biopsy prior to treatment is strongly recommended, unless it poses excessive risk 2. When biopsied, in addition to FFPE preparation, fresh tissue should be sent to VABHS for single-cell RNA sequencing and T-cell receptor sequencing 3. If baseline biopsy is not feasible, the most recent FFPE tumor tissue block from primary or metastatic sites should be obtained; if the block is unavailable, 15 (minimum 10) unstained slides are acceptable 4. If biopsy is deemed too risky, participation may proceed without new tissue. 11. Estimated life expectancy of at least 3 months 12. ECOG performance status ≤2 OR Karnofsky ≥60%. For the safety lead-in phase, only ECOG PS 0-1 patients will be included 13. Adequate bone marrow function, without recent transfusions or growth factor support (within 14 days prior to first dose): 1. Absolute neutrophil count \> 1,000/cubic millimeters (mm³) 2. Hemoglobin ≥ 9.0 grams (g)/deciliter (dL) 3. Platelets \> 100,000/mm³ 14. Adequate renal function: Estimated creatinine clearance ≥30 milliliter (mL)/minute (Cockcroft-Gault equation, actual weight), with no need for chronic dialysis. No capivasertib dose adjustment required if clearance ≥30 mL/minute 15. Adequate liver function: 1. Total bilirubin ≤1.5 × upper limit of normal value (ULN), or ≤3 × ULN for documented Gilbert's syndrome. 2. AST and ALT ≤2.5 × ULN (or ≤5 × ULN for hepatic metastases). 16. For females of childbearing potential: Negative serum pregnancy test at screening. 17. Male patients able to father children, and females of childbearing potential, must agree to use two highly effective contraceptive methods throughout the study and for at least 16 weeks after the last dose of capivasertib 18. Signed and dated informed consent indicating the patient has been fully informed about the study 19. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and all other study procedures Exclusion Criteria: 1. Patients who have undergone major surgery within 4 weeks, or major radiation therapy within 2 weeks, prior to starting treatment. Prior palliative radiotherapy is permitted if completed at least 48 hours before study entry 2. Receipt of another investigational agent within the past 4 weeks. Participation in observational studies is allowed 3. Persistent toxicities (CTCAE Grade ≥2) from previous anticancer therapy, except for alopecia. Patients with irreversible toxicity not reasonably expected to be exacerbated by study intervention (as deemed by the investigator, such as hearing loss) may be included. 4. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow capivasertib, or prior significant bowel resection that may impair adequate absorption, distribution, metabolism, or excretion of capivasertib. 5. Active tuberculosis infection, as determined by clinical evaluation, imaging, or tuberculosis testing per local practice 6. Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor 7. Known or suspected hypersensitivity to study drugs or any of their components 8. Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to study intervention Patients with previously treated CNS metastases may be eligible if they have recovered from acute effects of radiation or surgery, discontinued corticosteroids for at least 4 weeks, and are neurologically stable 9. Diagnosis of any other malignancy within the past 3 years, except adequately treated basal or squamous cell skin cancer, other Stage 0 or 1 cancers, or incidental prostate cancer found at cystoprostatectomy 10. Moderate to severe symptoms from metastatic cancer, including moderate to severe pain, impaired organ function, or spinal cord compression 11. Active autoimmune disease likely to worsen with ICI therapy. Patients with vitiligo, psoriasis, or thyroid disorders controlled without immunosuppressive therapy are eligible 12. Known severe hypersensitivity reactions (Grade \>3) to monoclonal antibodies, history of anaphylaxis, or uncontrolled asthma 13. History or concurrent condition of interstitial lung disease or severely impaired lung function, as judged by the investigator 14. Any of the following cardiac risks: 1. Mean resting corrected QT interval (QTc) \>470 milliseconds (ms) from triplicate ECGs at screening 2. History of QT prolongation due to medication requiring discontinuation 3. Congenital long QT syndrome, family history of long QT, or unexplained sudden cardiac death under age 40 in first-degree relatives 4. Significant arrhythmias (e.g., symptomatic or CTCAE Grade 3 PVCs, bigeminy, trigeminy, ventricular tachycardia), uncontrolled or symptomatic atrial fibrillation, unless well-controlled by medication or device (investigator and cardiologist review recommended) 5. Clinically significant electrolyte abnormalities linked to QTc prolongation: hypokalemia, hypomagnesemia, hypocalcemia 6. Any other condition(s) significantly increasing QTc prolongation risk per investigator judgment 7. History of coronary artery bypass, angioplasty, myocardial infarction, or unstable angina in the prior 3 months 8. Congestive heart failure (NYHA class ≥2) 15. Clinically significant abnormalities of glucose metabolism, including: 1. Type 1 or insulin-dependent type 2 diabetes 2. HbA1c \> 8.0% 16. Current or prior use of immunosuppressive medications within 7 days before study start, except: a. Intranasal, inhaled, topical steroids, or local injections (e.g., intra-articular) b. Systemic corticosteroids up to 10 mg/day of prednisone or equivalent c. Steroids as premedication for hypersensitivity (e.g., CT scan premedication) 17. Active bleeding diathesis. 18. Active infection requiring systemic therapy. 19. Positive for HIV infection or known AIDS, due to potential pharmacokinetic interactions with capivasertib. 20. Hepatitis B (positive surface antigen) or hepatitis C (positive HCV RNA if antibody positive). 21. Any other disease, condition, or laboratory abnormality which, in the investigator's opinion, may confound study results, increase the risks of study complications, contraindicate investigational drug use, or interfere with informed consent 22. Vaccination with live, attenuated, or unknown-status vaccines within 4 weeks of first study treatment or during the trial (except inactivated vaccines, e.g., inactivated influenza and COVID-19 vaccines) 23. Pregnancy, breastfeeding, or unwillingness/inability of female patients of childbearing potential and male patients to use two highly effective contraceptive methods throughout the study and for at least 16 weeks after the last dose of capivasertib 24. History of noncompliance with medical regimens 25. Unwillingness or inability to comply with study protocol