MEVPRO-1

This is a Phase 3, multicenter, randomized, open label study evaluating PF-06821497 in combination with enzalutamide versus physician’s choice of either second-line AR directed therapy with enzalutamide or docetaxel for participants with mCRPC after progression on priorabiraterone acetate. Participants may have received prior chemotherapy for mCSPC but are required to be chemotherapy naive in the castration-resistant setting. Participants who received prior treatment with 2nd generation ARSi’s in any setting (i.e. enzalutamide, apalutamide or darolutamide) will be excluded. This study consists of a Pre-Screening Phase, Screening Phase, Randomization, Treatment Phase, and Post-Treatment Phase. Participants will receive PF-06821497 in combination with enzalutamide (Arm A) or physician’s choice of comparator therapy of either enzalutamide or docetaxel (Arm B) in the Treatment Phase and will undergo procedures and assessments including regular safety and efficacy evaluations during the entire conduct of the study. The physician’s choice of agent in the control arm must be prespecified prior to randomization. 

 1. Participants aged ≥ 18 years (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 or signet cell features. For participants without a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis.

• Tumor tissue available (de novo or archived) for retrospective molecular profiling analysis.

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

• Measurable soft tissue disease is not required if there is an evaluable bone lesion.

• For participants with measurable soft tissue disease only, adenopathy below the aortic bifurcation alone does not qualify the participant for the study.

• Patients considered unevaluable are defined by meeting BOTH of the following criteria:

  o A bone scan referred to as a superscan showing an intense symmetric activity in the bones.

  o No soft tissue lesion (measurable or non-measurable) that can be assessed by RECIST 1.1.

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

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

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

• 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 must be ≥ 1 μg/L (1 ng/mL) (per PCWG-3 criteria);

• Soft tissue disease progression as defined by RECIST 1.1.

• Bone disease progression defined by Prostate Cancer Working Group (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan.

6. Treatment with abiraterone acetate is required in the mCSPC setting or first line mCRPC setting.

• In first line mCRPC, treatment with abiraterone plus Olaparib is permissible.

• Prior treatment with PARP monotherapy for BRCAm/HRRm gene mutated mCRPC following cancer progression on abiraterone is not permissible.

7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 

Participants with any of the following characteristics/conditions will be excluded:

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.

2. Clinically significant cardiovascular disease including a QTcF interval >480msec. (full details will be specified in the protocol).

3. CNS (central nervous system) pathology/neurological findings:

• Known or suspected brain metastasis or active leptomeningeal disease.

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

4. Any history of prior malignancy except for any of the following:

• Carcinoma in situ or non-melanoma skin cancer.

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

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

6. In the opinion of the investigator, any clinically significant gastrointestinal disorder affecting absorption or ability to swallow study treatments.

7. Known or suspected hypersensitivity to active ingredient/excipients of EZH2i or enzalutamide.

8. The following procedures and treatments are not permitted:

• Prior treatment at mCRPC stage for any cytotoxic chemotherapy, radioligand therapy, ARsi (enzalutamide, apalutamide, darolutamide), or other systemic anti-cancer treatment (including approved drugs or experimental compounds such as EZH2i, antibody therapy, gene therapy, angiogenesis inhibitors) with the following exceptions:

  o Treatment with ADT.

  o Treatment with first-generation antiandrogen agents (eg, bicalutamide, nilutamide, and flutamide), but there must be a washout period of 4 weeks prior to randomisation.

  o Docetaxel treatment during neoadjuvant/adjuvant treatment for localised prostate cancer and at mCSPC stage, as long as no signs of failure, or disease progression occurred during or immediately after such treatment.

9. 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), including their administration within 10 days or 5 half-lives, whichever is longer prior to randomization.

10. 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).

11. Major surgery (as defined by the investigator) within 2 weeks before randomization or palliative localized radiation therapy within 3 weeks before randomization.

12. Renal impairment as defined by:

• eGFR (< 45 mL/min/1.73m²). Based upon participant age at screening, eGFR is calculated using the recommended formula 2021 CKD-Epi (will be detailed further in protocol).

13. Hepatic dysfunction defined as:

• Total bilirubin ≥ 1.5 × ULN

• AST ≥ 2.5 × ULN

• ALT ≥ 2.5 × ULN

14. Hematologic abnormalities defined as:

• ANC ≤ 1500/mm3

• Platelets ≤ 100,000μL

• Hemoglobin ≤ 10 g/dL

15. 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