177Lu-PSMA-617 Therapy and Olaparib in Patients With Metastatic Castration Resistant Prostate Cancer (LuPARP)

• Drug: Olaparib
• Combination Product: 177Lu-PSMA

Inclusion Criteria

Patients must meet all of the following criteria for study entry:

1. Patient must be ≥ 18 years of age and must have provided written informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment..
2. Histologically confirmed adenocarcinomacancer arising from mucus-producing glands in organs of the prostate without neuroendocrine or small cell differentiation.
3. Eastern Cooperative Oncologythe study, diagnosis and treatment of cancer Group (ECOG) performance status of ≤ 1 (see Appendix 1).
4. For dosethe amount of medication taken escalation (dose levels 1-9) and expansion cohorts, patients must have had at least one prior line of taxane (docetaxel) chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells either in the hormonea chemical substance produced by glands in the endocrine system that regulates various functions in the body sensitive or castrate resistant setting unless the patient is deemed medically unsuitable for chemotherapy. If a patient has had docetaxel chemotherapy twice, this will be considered one line. For the continuous olaparib dose cohort (DE #2) patients can have had docetaxel however this is not required for eligibility.
5. Patients must have progressed on a second generation AR targeted agent (e.g. enzalutamide, abiraterone, darolutamide and/or apalutamide). Determination of disease progression on second generation AR targeted agent will be made by the local investigator.
6. Patients must have progressive disease for study entry. This is defined by PCWG3 as any one of the following:
   • PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement. The PSA value at screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening should be ≥ 10ng/ml.
   • Soft tissuetissue/the material that joins, holds up or surrounds inside body parts such as fat, muscle, ligaments and lining around joints or visceral disease progression as per RECIST 1.1 criteria (see Appendix 2)
   • Bone progression: ≥ 2 new lesions on bone scana type of medical imaging that uses a radioactive tracer to detect bone conditions or abnormalities (Appendix 2)
7. At least 3 weeks since the completion of surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence or radiotherapy prior to registration. Any clinically relevant sequelae from the surgery or radiotherapy must have improved to gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells 1 prior to registration.
8. Prior surgical orchiectomyremoval of one or both testicles, also known as orchidectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist). Patients without prior surgical castration must be currently taking and willing to continue luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) therapy throughout the duration of study treatment.
9. Serum testosterone levels ≤ 50ng/dL (≤ 1.75nmol/L) within 28 days before registration.
10. Imagingtests that create detailed images of areas inside the body evidence of metastatic disease documented with either bone scan or CT scan (Appendix 2).
11. Prior prostate cancer vaccine therapy, radiation therapya treatment that uses controlled doses of radiation to damage or kill cancer cells, systemic therapies, diethylstilboestrol (DES) or other estrogens, bicalutamide, flutamide or nilutamide are allowed up to 28 days prior to trial registration. Note: bicalutamide, flutamide or nilutamide must be discontinued within 4 weeks of registration.
12. Significant PSMA avidity on 68Ga/18F-PSMA PET/CT, defined as a minimum uptake of SUVmax 15 at a site of disease, and SUVmax > 10 at other sites of disease ≥10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact).
13. Patients must have a life expectancy ≥ 24 weeks.
14. Patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception (see section 11.7.4 for acceptable methods).
15. Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled assessments including completing Patient Reported Outcomes (PRO) instruments.
16. Patients must have adequate bone marrowsoft, spongy tissue found in bones that makes blood cells, hepatic and renal function documented within 28 days prior to registration, defined as:
    • Haemoglobin ≥ 100 g/L independent of transfusions (no red bloodthe red bodily fluid that transports oxygen and other nutrients around the body cell transfusion in last 8 weeks)
    • Absolute neutrophil count ≥ 1.5×109/L
    • Plateletssmall disc-shaped blood cells that clump together to form clots to stop bleeding ≥ 150 x109/L
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert’s syndrome where this applies for the unconjugated bilirubin.
    • Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT) ≤ 2.5 x ULN if there is no evidence of liver metastasiswhen the cancer has spread to other parts of the body, also known as mets or ≤ 5 x ULN in the presence of liver metastases.
    • Albumin ≥ 30 g/L
    • Adequate renal function: patients must have creatinine clearance estimated of ≥ 51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test to appendix 5).
17. Patients who are deemed by PSMA imaging to have readily accessible disease will be required to consent to 3 serial tumoura tissue mass that forms from groups of unhealthy cells biopsies – at screening, post combination treatment (at any time between weeks 2-4) and in the event of disease progression.