MEVPRO-3

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 of age or older (or the minimum age of consent in accordance with local regulations) at screening. 

2. Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features (neuroendocrine differentiation and other histologic components are permitted if adenocarcinoma is the primary histology). For participants without a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis.

3. Metastatic prostate cancer documented by positive bone scan (for bone disease) or metastatic lesion(s) on CT or MRI scan (for soft tissue/visceral disease).

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

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

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

d. A bone scan showing intense symmetric activity in the bones (referred to as a superscan) is not considered evaluable.

4. Resolution of acute effects of any prior therapy to either baseline severity or CTCAE Grade ≤1 (except for AEs which do not constitute a safety risk in the investigator’s judgement).

Allowed Prior Treatments:

5. Participants cannot have received any cytotoxic chemotherapy, ARPIs (eg, enzalutamide, apalutamide, abiraterone acetate, or darolutamide), any other systemic anticancer therapies for mCSPC, with the following exceptions:

a. ADT (chemical or surgical) must be started prior to randomization and must continue throughout the study. Prior therapy with up to 3 months of ADT.(with or without antiandrogens) is allowed with no radiographic evidence of 

disease progression or rising PSA levels prior to Day 1. 

b. Treatment with estrogens, cyproterone acetate or first-generation antiandrogens is allowed until randomization, but must be discontinued prior to randomization.

c. Participants may have received 1 course of palliative radiation or surgery for symptomatic control secondary to prostate cancer, which should be completed at least 2 weeks prior to randomization. 

Note: Radical prostatectomy or definitive radiotherapy to the primary prostate tumor for mCSPC with curative intent is not permitted. 

Other Inclusion criteria:

6. Participants must have ECOG PS 0. 

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 judgment, make the participant inappropriate for the study. 

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

b. Participants with known HIV or AIDS-related illness, or active hepatitis B or 

C are excluded. 

Active HBV is defined as any of the following:

 HBsAg reactive or detectable [qualitative] HBV DNA

Note: Participants who are HBsAg(-), HBcAb(+) are eligible and should be monitored/treated as per local standard of care. 

Active HCV is defined as:

 Detectable [qualitative] HCV RNA

c. Participants with a known history of 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 are excluded. 

d. Participants with a known history of active inflammatory gastrointestinal disease, chronic diarrhea, or previous gastric resection or lap-band surgery are excluded.

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, or other clinically significant cardiovascular disease as assessed bythe investigator. If a participant has a cardiac rhythm device/pacemaker placed and QTcF >470 ms, the participant may be considered eligible. QTcF >480 ms 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 nonmelanoma 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.

5. In the opinion of the investigator, any clinically significant gastrointestinal disorder 

affecting absorption. 

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

Administrator: Oncology Research Team