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

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 consent.

2. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine orsmall cell differentiation.

3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (see Appendix 1).

4. For dose escalation (dose levels 1-9) and expansion cohorts, patients must have hadat least one prior line of taxane (docetaxel) chemotherapy either in the hormonesensitive or castrate resistant setting unless the patient is deemed medicallyunsuitable for chemotherapy. If a patient has had docetaxel chemotherapy twice, thiswill 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 ofdisease progression on second generation AR targeted agent will be made by the localinvestigator.

6. Patients must have progressive disease for study entry. This is defined by PCWG3 asany one of the following:

• PSA progression: minimum of two rising PSA values from a baseline measurementwith an interval of ≥ 1 week between each measurement. The PSA value atscreening should be ≥ 10ng/ml.

• Soft tissue or visceral disease progression as per RECIST 1.1 criteria (seeAppendix 2)

• Bone progression: ≥ 2 new lesions on bone scan (Appendix 2)

7. At least 3 weeks since the completion of surgery or radiotherapy prior toregistration. Any clinically relevant sequelae from the surgery or radiotherapy musthave improved to grade 1 prior to registration.

8. Prior surgical orchiectomy or chemical castration maintained on luteinizinghormone-releasing hormone (LHRH) analogue (agonist or antagonist). Patients withoutprior surgical castration must be currently taking and willing to continueluteinizing 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 beforeregistration.

10. Imaging evidence of metastatic disease documented with either bone scan or CT scan (Appendix 2).

11. Prior prostate cancer vaccine therapy, radiation therapy, systemic therapies,diethylstilboestrol (DES) or other estrogens, bicalutamide, flutamide or nilutamideare allowed up to 28 days prior to trial registration. Note: bicalutamide, flutamideor nilutamide must be discontinued within 4 weeks of registration.

12. Significant PSMA avidity on 68Ga/18F-PSMA PET/CT, defined as a minimum uptake ofSUVmax 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 ofolaparib when having sexual intercourse with a pregnant woman or with a woman ofchildbearing potential. Female partners of male patients should also use a highlyeffective 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 ofthe study including undergoing treatment, scheduled assessments including completingPatient Reported Outcomes (PRO) instruments.

16. Patients must have adequate bone marrow, hepatic and renal function documentedwithin 28 days prior to registration, defined as:

• Haemoglobin ≥ 100 g/L independent of transfusions (no red blood celltransfusion in last 8 weeks)

• Absolute neutrophil count ≥ 1.5x109/L

• Platelets ≥ 150 x109/L

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients withknown Gilbert's syndrome where this applies for the unconjugated bilirubin.

• Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT) ≤ 2.5x ULN if there is no evidence of liver metastasis or ≤ 5 x ULN in the presenceof 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 testto appendix 5).

17. Patients who are deemed by PSMA imaging to have readily accessible disease will berequired to consent to 3 serial tumour biopsies - at screening, post combinationtreatment (at any time between weeks 2-4) and in the event of disease progression.

Exclusion Criteria:

Patients must not meet any of the following criteria for study entry:

1. Site(s) of disease that are FDG positive with low PSMA expression defined by PSMASUVmax < 10.

2. Extensive marrow disease defined by a "Super Scan" on bone scintigraphy or diffusemarrow infiltration on PSMA PET.

3. Previous history or presence of brain metastases or leptomeningeal metastases. Ascan to confirm the absence of brain metastases is not required if there is noclinical history of this.

4. Surgery or radiotherapy within < 3 weeks of registration (except for palliativereasons). Patients must have recovered from any effects of any major surgery.

5. Patients with symptomatic or impending cord compression unless appropriately treatedbeforehand and clinically stable for ≥ 4 weeks.

6. Any prior exposure to 177Lu-PSMA, cabazitaxel, platinums, PARP inhibitors,mitoxantrone or cyclophosphamide.

7. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, recent thromboembolic events (<6 months ago), uncontrolled major seizuredisorder, unstable spinal cord compression, superior vena cava syndrome, extensiveinterstitial bilateral lung disease on High Resolution Computed Tomography (HRCT)scan or psychiatric illness/social situations that is likely to impede participationand /or compliance in the study.

8. Persistent toxicities [Common Terminology Criteria for Adverse Event (CTCAE) ≥ grade 2] caused by previous cancer therapy, excluding alopecia.

9. Other malignancies within the previous 2-years other than basal cell or squamouscell carcinomas of skin or other cancers that are unlikely to recur within 24months.

10. Previous history of interstitial lung disease or non-infectious pneumonitis.

11. Patients with a history or clinical features suggestive of myelodysplastic syndrome / acute myeloid leukaemia.

12. Patients unable to swallow orally administered medications or with gastrointestinaldisorders likely to interfere with the absorption of the study medication.

13. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, asjudged by the investigator (e.g., unstable ischemia, uncontrolled symptomaticarrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolytedisturbances, etc.), or patients with congenital long QT syndrome.

14. Known hypersensitivity to olaparib or any of the excipients of olaparib.

15. Immunocompromised patients, e.g., patients who are known to be serologicallypositive for human immunodeficiency virus (HIV1/2). Only need to check this if thereis a clinical history. HIV-infected (HIV1/2 antibody-positive) patients mayparticipate if they meet all the following eligibility requirements:

• They must be on an anti-retroviral regimen with evidence of at least twoundetectable viral loads within the past 6 months on this same regimen; themost recent undetectable viral load must be within the past 12 weeks.

• They must have a CD4 count ≥ 250 cells/µL over the past 6 months on this sameanti-retroviral regimen and must not have had a CD4 count < 200 cells/µl overthe past 2 years, unless it was deemed related to the cancer and/orchemotherapy-induced bone marrow suppression.

• For patients who have received chemotherapy in the past 6 months, a CD4 count < 250 cells/µl during chemotherapy is permitted as long as viral loads wereundetectable during this same chemotherapy.

• They must have an undetectable viral load and a CD4 count ≥ 250 cells/µL within 7 days of enrolment.

• They must not be currently receiving prophylactic therapy for an opportunisticinfection and must not have had an opportunistic infection within the past 6months.

16. Patients with known active hepatitis (i.e. Hepatitis B or C). Only need to checkthis if there is a clinical history.

• Active hepatitis B virus (HBV) is defined by a known positive HBV surfaceantigen (HBsAg) result. Patients with a past or resolved HBV infection (definedas the presence of hepatitis B core antibody and absence of HBsAg) areeligible.

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction is negative for HCV RNA.

17. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The requiredwashout period prior to starting olaparib is 2 weeks.

18. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) ormoderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washoutperiod prior to starting olaparib is 5 weeks for phenobarbital and enzalutamide and 3 weeks for other agents.

19. Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT).

20. Participation in another clinical study with an investigational product or anothersystemic therapy administered in the last 3 weeks.