Trial of Pembrolizumab in Metastatic Castration Resistant Prostate Cancer

Inclusion Criteria:

1. Male, aged 18 years or older.

2. Histologically confirmed metastatic castrate resistant adenocarcinoma of the prostate.If the patient does not have a prior histological diagnosis then the planned baselinefresh biopsy may be used for both the purpose of confirming the histological diagnosisprior to trial entry and for subsequent biomarker analysis. All patients must bewilling to have fresh biopsies to obtain tumour tissue for biomarker analysis.

3. Identified high mutational load (defined as 11 or more mutations per targeted panel -see Section 5.5 below) on next generation sequencing and/or a DNA repair defect thatcan increase mutation load including MMR deficiency and/or high MSI by next generationsequencing.

4. Patients with no measurable disease and only widespread bone disease must have a CTCcount >5.

5. Willing and able to comply with the follow-up schedule and the requirements of thebiomarker studies including the paired fresh tumour biopsies.

6. Written informed consent.

7. Prior treatment with at least one of the approved treatments for mCRPC (i.e.Abiraterone, Enzalutamide, Docetaxel, Cabazitaxel, Radium 223).

8. At least 28-days washout at trial entry since the completion of prior therapy,including major surgery, chemotherapy and other investigational agents. For hormonaltreatment and radiotherapy refer to the guidelines below:

• At least 28-days since the completion of prior flutamide treatment. Patients whosePSA did not decline in response to antiandrogens given as a second line or laterintervention will only require a 14-day washout prior to Cycle 1, Day 1.

• At least 42-days since the completion of prior bicalutamide (Casodex) andnilutamide (Nilandron) treatment. Patients whose PSA did not decline for at least 3-months in response to antiandrogens given as second line or later interventionwill require only a 14-day washout period prior to Cycle 1 Day 1.

• At least 14-days from any radiotherapy with the exception of a single fraction ofradiotherapy for the purposes of palliation (confined to one field) is permitted.

9. Documented prostate cancer progression as assessed by the investigator with one of thefollowing:

• PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1-week between each determination. The PSA value at the Screening visit should be ≥ 2 µg/L (2 ng/ml) if there is no measurable disease; patients on systemicglucocorticoids for control of symptoms must have documented PSA progression by PCWG3while on the same dose of systemic glucocorticoids prior to commencing Cycle1 Day1 oftreatment.

• Radiographic progression of soft tissue disease by iRECIST criteria or of bonemetastases by PCWG3 criteria with two or more confirmed new bone lesions on a bonescan/wb-MRI with or without PSA progression.

10. Surgically or medically castrated, with testosterone levels of <50 ng/dL (<2.0 nM). Ifthe patient is being treated with LHRH agonists (patient who have not undergoneorchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1Day 1 and must be continued throughout the study.

11. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

12. Albumin ≥25 g/L.

13. Patient and the patient's partner of reproductive potential who are sexually active,must agree to use adequate methods of contraception during the course of the study andfor 120 days after the last dose of study drug (see appendix A3 for accepted methodsof contraception).

14. QT interval corrected for heart rate according to Fridericia's formula (QTcF) <470msec or <480 msec with bundle branch block.

15. Patients with primary hypothyroidism can be considered eligible if thyroid stimulatinghormone (TSH) at the screening visit is within normal range while patient is underhormonal treatment.

16. Subjects must have adequate bone marrow, hepatic and renal function documented within 7-days of trial entry defined as: Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L International normalised ratio (INR) ≤ 1.5x upper limit of normal (ULN) Or:Prothrombin time ≤ 1.5x upper limit of normal (ULN) Serum bilirubin (for patients withtotal bilirubin >1.5x ULN) Or: Direct bilirubin ≤ 1.5x ULN ≤1.5x ULN Alanineaminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x ULN (for patients withliver metastases ≤ 5x ULN is permissible) Serum creatinine ≤1.5 x ULN Or: Calculatedcreatinine clearance >40mL/min for patients with creatinine levels above institutionalnormal. For GFR estimation, the Cockcroft and Gault equation should be used: creatinineclearance = (((140 - age) x mass (kg)) x 1.23) / serum creatinine (µ mol⁄L)

Exclusion Criteria:

• 1. Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2,anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies.

2. Patients who have received any of the following concomitant therapies: IL-2,interferon or other non-study immunotherapy regimens; immunosuppressive agents; otherinvestigational therapies; or chronic use of systemic corticosteroids (used in themanagement of cancer or non-cancer-related illnesses) within 1 week prior to firstdose. A dose of 10mg of prednisolone or equivalent will be allowed if clinicallyindicated.

3. Patients who have received any non-oncology vaccine therapy used for prevention ofinfectious diseases including seasonal vaccinations for up to 28-days prior to theexpected start or after any dose of pembrolizumab. Examples include, but are notlimited to, the following: measles, mumps, rubella, chicken pox, yellow fever,seasonal flu, H1N1 flu, rabies, BCG, and typhoid vaccine.

4. Patients receiving growth factors including, but not limited to, granulocyte colonystimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF),erythropoietin, within 14-days of study drug administration. Use of such agents whileon study is also prohibited. Prior use of growth factors should be documented in thepatient's medical history.

5. Uncontrolled intercurrent cardiovascular disease as symptomatic congestive heartfailure (New York Heart Association Class III or IV heart disease), unstable anginapectoris, cardiac arrhythmia, poorly controlled hypertension (defined as systolicblood pressure of ≥150mmHg or diastolic blood pressure of >100 mmHg based on a mean ofthree measurements at approximately 2-minute intervals).

6. Any psychiatric illness/social situations that would limit compliance with studyrequirements.

7. Any acute toxicity due to prior chemotherapy and / or radiotherapy that has notresolved to a NCI-CTCAE v4 grade ≤1 with the exception of chemotherapy inducedalopecia and grade 2 peripheral neuropathy.

8. Prior malignancy diagnosed within the previous 2-years with a >30% probability ofrecurrence within 12-months, with the exception of non-melanoma skin cancer, andin-situ or non-muscle invasive bladder cancer.

9. Patients with myelodysplastic syndrome or acute myeloid leukaemia. 10. Patientswith known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participate providedthey are stable (without evidence of progression by imaging for at least four weeksprior to the first dose of trial treatment and any neurologic symptoms have returnedto baseline), have no evidence of new or enlarging brain metastases, and are not usingsteroids for at least 7 days prior to trial treatment. This exception does not includecarcinomatous meningitis which is excluded regardless of clinical stability.

10. Patients with symptomatic or impending cord compression unless appropriatelytreated beforehand and clinically stable and asymptomatic.

11. Any chronic respiratory disease. 13. Any immunological disorder requiringtreatment with immunosuppressive treatments:

• High dose of steroids (low dose of steroids as 10mg of prednisolone or equivalentare allowed if the patient is not able to discontinue this treatment; patient needs tobe on a stable dose for at least 4-weeks before the enrolment);

• Cytotoxic agents (such as alkylating agents or antimetabolites);

• Antibodies (polyclonal antibodies; monoclonal antibodies different frompembrolizumab);

• Drugs acting on immunophilins (cyclosporin, tacrolimus, sirolimus);

• Other drugs (interferons, TNF binding proteins, mycophenolate). 14. History ofany autoimmune disease: patients with a history of inflammatory bowel disease,including ulcerative colitis and Crohn's Disease, are excluded from this study,as are patients with a history of symptomatic disease (e.g., rheumatoidarthritis, systemic progressive sclerosis [scleroderma], systemic lupuserythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); CNS ormotor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndromeand myasthenia gravis, multiple sclerosis). Patients with controlled Graves'disease will be allowed.

15. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 16.Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

16. History of congenital platelet function defect (e.g., Bernard-Souliersyndrome, Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pooldefect).

17. Patients with history of (non-infectious) pneumonitis that required steroidsor current pneumonitis.

18. Initiating bisphosphonate therapy or adjusting bisphosphonate dose/regimenwithin 30 days prior to Cycle 1 Day 1. Patients on a stable bisphosphonateregimen are eligible and may continue.

19. Presence of a condition or situation, which, in the investigator's opinion,may put the patient at significant risk, may confound the study results, or mayinterfere significantly with the patient's participation in the study.