MEVPRO-2

A Study to Learn About the Investigational Medicine Called PF-06821497 in Men with Metastatic Castration-Resistant Prostate Cancer Who Have Not Tried Novel Hormonal Therapy or Chemotherapy for Metastatic Prostate Cancer. The rationale of this study is to evaluate whether the addition of EZH2 (enhancer of zeste homologue-2) inhibition to enzalutamide can delay or prevent anti-androgen resistance, thereby increasing the duration of clinical benefit of enzalutamide in patients who are treatment naïve to androgen receptor signaling inhibitors (ARSi’s) or abiraterone and have not yet received chemotherapy in the mCRPC (metastatic castration resistant prostate cancer) setting. This Phase 3 randomized study (C2321003) is designed to demonstrate that PF06821497 plus enzalutamide provides superior clinical benefit compared to enzalutamide in patients with mCRPC 

Participants are eligible to be included in this study only if all of the following criteria apply:

Age and Sex:

1. Male participants aged ≥ 18 years (or the minimum age of consent in accordance with local regulations) at screening.

  a. Refer to Appendix 4 for reproductive criteria for male participants (Section 10.4.1).

Disease Characteristics:

2. Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features. For participants without a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis.

3. Metastatic disease in bone documented on bone scan, or in soft tissue documented on CT/MRI scan.

  a. Measurable soft tissue disease (per RECIST v1.1) is required if there is not an evaluable bone lesion (per PCWG3 criteria).

    o PET and SPECT are not evaluable imaging modalities for this study.

    o A bone scan referred to as a super scan showing an intense symmetric activity in the bones is not considered evaluable.

  b. For participants with measurable soft tissue disease only, regional lymph node disease (ie, those below the aortic bifurcation) alone does not qualify the participant for the study.

4. Surgically or medically castrated, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.

  a. Ongoing androgen deprivation therapy with a GnRH agonist or antagonist for participants who have not undergone bilateral orchiectomy must have been initiated at least 4 weeks before randomization and must continue throughout the study.

NOTE: Participants who are not orchiectomized will also continue to receive a GnRH (gonadotropin releasing hormone) agonist or antagonist on study.

5. Progressive disease in the setting of medical or surgical castration as defined by meeting 1 or more of the following 3 criteria:

  a. PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination, with a PSA value at the Screening visit being ≥ 2 µg/L (1 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression) (per PCWG-3 criteria).

  b. Soft tissue disease progression as defined by RECIST 1.1.

  c. Bone disease progression defined by PCWG3 with 2 or more new metastatic bone lesions on a whole-body radionuclide bone scan.

6. Prior to randomization, there must be resolution of acute effects of any prior therapy to either baseline severity or CTCAE Grade ≤ 1 (except for AEs such as alopecia and peripheral neuropathy not constituting a safety risk in the investigator’s judgement).

Other Inclusion criteria:

7. ECOG performance status 0 or 1, with a life expectancy of ≥ 12 months as assessed by the investigator. 

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions:

1. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgement, make the participant inappropriate for the study.

  a. HIV/HBV/HCV testing is not required unless mandated by local health authority.

  b. Participants with known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness, or active hepatitis B or C are excluded.

  c. Chronic liver diseases including alcoholic liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, Wilson’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, or other chronic liver disease.

2. Clinically significant cardiovascular disease, defined as:

  a. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Class III or IV), cerebrovascular accident, or symptomatic pulmonary embolism or other clinically significant episode of thromboembolic disease, congenital long QT syndrome, Torsade de Pointes, clinically important arrhythmias, left anterior hemiblock (bifascicular block), ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2, atrial fibrillation of any grade.

  b. Cardiac rhythm device/pacemaker. Participants with cardiac rhythm device/pacemaker must be discussed in detail with sponsor medical monitor to determine eligibility.

  c. QTcF > 480 msec on screening ECG.

3. CNS pathology/neurological findings:

  a. Known or suspected brain metastasis or active leptomeningeal disease.

  b. Symptomatic or impending spinal cord compression or cauda equina syndrome.

  c. Participants with epidural disease, canal disease and prior cord involvement are NOT excluded if those areas have been treated, are stable, and not neurologically impaired.

  d. Clinically significant history of seizure or any condition that may predispose to seizure (eg, prior cortical stroke, significant brain trauma). Also, history of unexplained loss of consciousness or transient ischemic attack within 12 months of randomization.

4. Any history of myelodysplastic syndrome, acute myeloid leukemia, or any other prior malignancy except for any of the following:

  a. Carcinoma in situ or non-melanoma skin cancer.

  b. Any prior malignancies ≥ 3 years before randomization with no subsequent evidence of recurrence or progression regardless of the stage.

  c. Stage 0 or Stage 1 cancer < 3 years before randomization that has a remote probability of recurrence or progression in the opinion of the investigator.

Prior/Concomitant Therapy:

5. Participants must be treatment naïve at the mCRPC stage, eg, participants cannot have received any cytotoxic chemotherapy (includes but not limited to docetaxel), received ARSI/ abiraterone acetate in mCRPC, mCSPC or non-metastatic PC. Prior docetaxel in mCSPC is allowed.

  a. The following treatments are not allowed; enzalutamide, apalutamide, darolutamide, abiraterone acetate, EZH2 inhibitors, or other systemic treatment (approved drugs or experimental compounds), prednisone > 10 mg/day (or equivalents) for prostate cancer, with the following exceptions:

    o Treatment with first-generation antiandrogen (ADT) agents (eg, bicalutamide, nilutamide, and flutamide), but there must be a washout period of 28 days prior to randomization.

    o Docetaxel treatment is allowed for mCSPC , as long as no signs of failure, or disease progression occurred during treatment or within 3 months of treatment completion.

    o Biologic therapy including sipuleucel-T, or radionuclide therapy received in the castration-sensitive prostate cancer if discontinued in the 28 days prior to or at randomization and no signs of failure or disease progression occurred during or immediately after such treatment.

6. Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to randomization are not permitted.

7. Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).

8. Current use or anticipated need for drugs that are known strong CYP3A4/5 inhibitors and inducers (with exception of enzalutamide as part of this study) outlined in Section 6.9.1 and Section 6.9.2, including their administration within 10 days or 5 half-lives, whichever is longer prior to randomization.

9. Major surgery or palliative localized radiation therapy within 14 days before randomization.

Diagnostic Assessments:

10. Inadequate renal function defined by an eGFR < 5 mL/min. Based upon participant age at screening, eGFR is calculated using the recommended formulas in Section 10.7.1 to determine eligibility and to provide a baseline to quantify any subsequent kidney safety events.

  For eligibility assessment based upon estimated renal function, the higher of the screening and baseline eGFR values may be used.

11. Hepatic dysfunction defined as:

  a. Total bilirubin ≥ 1.5 × ULN

  b. AST > 2.5 × ULN

  c. ALT > 2.5 × ULN.

12. Hematologic abnormalities defined as:

  a. ANC < 1500/mm3

  b. Platelets < 100,000/µL

  c. Hemoglobin ≤ 9 g/dL, independent of transfusion within 14 days of randomization.

Other Exclusion Criteria:

13. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family

members. 

Research Nurse: Rachel Bolton (Rachel.bolton@elht.nhs.uk)

Administrator: Oncology Research Team