Brief Summary:
This is a phase 3, randomized, open-label study of opevesostat compared to alternative
abiraterone acetate or enzalutamide in participants with metastatic castration-resistant
prostate cancer (mCRPC) with respect to overall survival (OS) and to radiographic
progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG) Modified
Response Evaluation Criteria In Solid Tumors (RECIST 1.1) as assessed by blinded
independent central review (BICR) in participants with mCRPC previously treated with
next-generation hormonal agent (NHA) and taxane-based chemotherapy. It is hypothesized
that opevesostat is superior with respect to OS and rPFS per PCWG Modified RECIST 1.1 as
assessed by BICR in androgen receptor ligand binding domain (AR LBD) mutation-negative
and -positive participants.
Inclusion Criteria:
- Has histologically- or cytologically-confirmed adenocarcinoma of the prostate
without small cell histology
- Has prostate cancer progression while on androgen deprivation therapy (or post
bilateral orchiectomy) within 6 months before Screening
- Has current evidence of metastatic disease documented by either bone lesions on bone
scan and/or soft tissue disease by computed tomography/magnetic resonance imaging
(CT/MRI)
- Has disease that progressed during or after treatment with 1 novel hormonal agent
(NHA)
- Has received 1 but no more than 2 taxane-based chemotherapy regimens for metastatic
castration-resistant prostate cancer (mCRPC) and has had progressive disease (PD)
during or after treatment
- Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nM)
- Has provided tumor tissue from a fresh core or excisional biopsy from soft tissue
not previously irradiated
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
assessed within 7 days of randomization
- Has had prior treatment with PARPi or were deemed ineligible to receive treatment by
the investigator or have refused PARPi treatment
- Has received prior 177Lu-PSMA-617 or were deemed ineligible to receive
177Lu-PSMA-617 treatment by the investigator or refused 177Lu-PSMA-617 treatment
- Participants who have not received cabazitaxel can be enrolled if they are
ineligible for cabazitaxel treatment as determined by the investigator or have
refused treatment
- If participant received first generation anti-androgen therapy before screening, the
participant has evidence of disease progression >4 weeks since the last flutamide
treatment and >6 weeks since the last bicalutamide or nilutamide treatment
- Participants receiving bone resorptive therapy (including, but not limited to,
bisphosphonate or denosumab) must have been on stable doses for ≥ 4 weeks before the
date of randomization
- Participants with human immunodeficiency virus (HIV) infection must have well
controlled HIV on antiretroviral therapy (ART)
- Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if
they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks
and have undetectable HBV viral load before randomization
- Participants with history of hepatitis C virus (HCV) infection are eligible if HCV
viral load is undetectable at Screening.
- Participants who can produce sperm must agree to the following during the study
treatment period and for at least 7 days after the last dose of opevesostat, for at
least 30 days after the last dose of abiraterone acetate, and for at least 3 months
after the last dose of enzalutamide: EITHER be abstinent OR must agree to use male
condom
Exclusion Criteria:
- Has a gastrointestinal disorder that might affect absorption
- Has a history of pituitary dysfunction
- Has poorly controlled diabetes mellitus
- Has clinically significant abnormal serum potassium or sodium level
- Has a history of active or unstable cardio/cerebro-vascular disease, including
thromboembolic events
- Has a history of seizure within 6 months of providing documented informed consent or
any condition that may predispose to seizures within 12 months before the date of
randomization
- Has a history of clinically significant ventricular arrhythmias
- Has received an anticancer monoclonal antibody (mAb) within 4 weeks before the date
of randomization, or has not recovered from adverse events (AEs) due to mAbs
administered more than 4 weeks before the date of randomization
- Has undergone major surgery, including local prostate intervention (except prostate
biopsy), within 28 days before the date of randomization, and has not recovered from
the toxicities and/or complications
- Participants who have not adequately recovered from major surgery or have ongoing
surgical complications
- Has used herbal or medicinal products that may have hormonal anti-prostate cancer
activity and/or are known to decrease prostate-specific Antigen (PSA) (eg, saw
palmetto, megesterol acetate) within 4 weeks before the date of randomization
- Has received radium-223 or lutetium-177 within 4 weeks before the date of
randomization, or has not recovered to Grade ≤1 or baseline from AEs due to
radium-223 or lutetium-177 administered more than 4 weeks before the date of
randomization
- Has received treatment with 5-αreductase inhibitors (eg, finasteride or
dutasteride), estrogens, or cyproterone within 4 weeks before the date of
randomization
- Has received colony-stimulating factors within 28 days before the date of
randomization
- Has received a whole blood transfusion in the last 120 days before the date of
randomization. Packed red blood cells and platelet transfusions are acceptable if
not given within 28 days of the date of randomization
- Has received prior targeted small molecule therapy or NHA treatment within 4 weeks
before the first dose of study intervention as follows: enzalutamide or apalutamide
within 3 weeks or abiraterone acetate + prednisone or darolutamide within 2 weeks
- Has a "superscan" bone scan
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior the first dose of
study medication
- Has a known additional malignancy that is progressing or has required active
treatment within the past 3 years
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis
- Has an active autoimmune disease that has required systemic treatment in past 2
years
- Has an active infection requiring systemic therapy
- Has concurrent active HBV or known active HCV infection
- Has a history of long QTc syndrome
- Has any of the following at Screening Visit: hypotension (systolic BP <110 mm Hg) or
uncontrolled hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥90 mm Hg, in 2
out of 3 recordings with optimized antihypertensive therapy)
- Is unable to swallow capsules/tablets
- Is currently being treated with cytochrome 450-inducing antiepileptic drugs for
seizures
- Participants on an unstable dose of thyroid hormone therapy within 6 months before
the start of the study intervention
- Received prior systemic anticancer therapy including investigational agents within 4
weeks before the first dose of study intervention
- Received prior radiotherapy within 2 weeks of start of study intervention, or
radiation-related toxicities, requiring corticosteroids
- Received a live or live-attenuated vaccine within 30 days before the first dose of
study intervention
- Systemic use of the following medications within 2 weeks before the first dose of
study intervention: strong CYP3A4 inducers (eg, avasimibe, carbamazepine,
lumacaftor, phenobarbital, rifampicin, rifapentine, or St John's Wort); P-gp
inhibitors (eg, erythromycin, clarithromycin, rifampicin, ketoconazole,
itraconazole, posaconazole, artesunate-pyronaridine, ritonavir, indinavir,
nelfinavir, atazanavir, glecaprevir-pibrentasvir, simeprevir, ledipasvir-sofosbuvir,
verapamil, diltiazem, dronedarone, propafenone, quinidine, cyclosporine, valspodar,
or milk thistle [Silybum marianum])
- Use of aldosterone antagonist (eg, spironolactone, eplerenone) and phenytoin within
4 weeks before the start of the study intervention
Primary outcome:
1. Overall Survival (OS) in Androgen Receptor Ligand Binding Domain (AR LBD) Mutation-Positive Participants (Time Frame - Up to ~54 months):
OS is defined as time from randomization to death due to any cause. OS in AR LBD
mutation-positive participants will be reported for each study arm.
2. OS in AR LBD Mutation-Negative Participants (Time Frame - Up to ~54 months):
OS is defined as time from randomization to death due to any cause. OS in AR LBD
mutation-negative participants will be reported for each study arm.
3. Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review in AR LBD Mutation-Positive Participant (Time Frame - Up to ~36 months):
rPFS is defined as the time from randomization to the first documented disease
progression per Prostate Cancer Working Group (PCWG)-modified Response Evaluation
Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent
Central Review (BICR) or death due to any cause, whichever occurs first. rPFS in AR LBD
mutation-positive participants will be reported for each study arm.
4. rPFS Per Prostate Cancer Working Group-modified RECIST 1.1 as Assessed by Blinded Independent Central Review in AR LBD Mutation-Negative Participants (Time Frame - Up to ~36 months):
rPFS is defined as the time from randomization to the first documented disease
progression per PCWG-modified RECIST 1.1 as assessed by BICR or death due to any cause,
whichever occurs first. rPFS in AR LBD mutation-negative participants will be reported
for each study arm.
Secondary outcome:
1. Time to Initiation of the First Subsequent Anti-Cancer Therapy or Death (TFST) (Time Frame - Up to ~54 months):
TFST is defined as the time from randomization to initiation of the first subsequent
anticancer therapy or death, whichever occurs first.
2. Objective Response (OR) (Time Frame - Up to ~54 months):
OR is determined by PCWG-modified RECIST 1.1 as assessed by BICR.
3. Duration of Response (DOR) (Time Frame - Up to ~54 months):
DOR is determined by PCWG-modified RECIST 1.1 as assessed by BICR.
4. Time to Pain Progression (TTPP) (Time Frame - Up to ~54 months):
TTPP is assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24
Hours") and opiate analgesic use (Analgesic Quantification Algorithm [AQA] Score).
5. Time to Prostate-specific Antigen (PSA) Progression (Time Frame - Up to ~54 months):
The time from randomization to PSA progression. The PSA progression date is defined as
the date of either: 1) ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second
value ≥3 weeks later if there is PSA decline from baseline 2) ≥25% increase and ≥2 ng/mL
increase from baseline beyond 12 weeks if there is no PSA decline from baseline.
6. Time to First Symptomatic Skeletal-related Event (SSRE) (Time Frame - Up to ~54 months):
The time from randomization to the first occurrence of any of the following symptomatic
skeletal-related events: 1) Use of EBRT to prevent or relieve skeletal symptoms; 2) new
symptomatic pathologic bone fracture (vertebral or nonvertebral); 3) spinal cord
compression; or 4) tumor-related orthopedic surgical intervention.
7. Number of Participants Who Experience an Adverse Event (Time Frame - Up to ~54 months):
An AE is any untoward medical occurrence in a clinical study participant, temporally
associated with the use of study intervention, whether or not considered related to the
study intervention.
8. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (Time Frame - Up to ~54 months):
An AE is any untoward medical occurrence in a clinical study participant, temporally
associated with the use of study intervention, whether or not considered related to the
study intervention.
- Experimental: Opevesostat
Participants receive opevesostat 5 mg by oral tablets twice daily (bid) plus
dexamethasone 1.5 mg by oral tablets once daily (qd) and 0.1 mg fludrocortisone acetate
by oral tablet qd until progression. Hydrocortisone 100 mg (oral or intramuscular [IM])
dose will also be provided to participants for use as rescue medication. - Active Comparator: Abiraterone Acetate or Enzalutamide
Participants receive abiraterone 1000 mg qd by oral tablets plus prednisone 5 mg bid by
oral tablets or enzalutamide 160 mg qd by oral tablets.
- Opevesostat (MK-5684):
Administered orally - Abiraterone acetate (ZYTIGA / YONSA / ):
Administered orally - Enzalutamide (XTANDI):
Administered orally - Hydrocortisone:
Administered orally or IM as a rescue medication - Fludrocortisone acetate:
Administered orally - Prednisone:
Administered orally - Dexamethasone:
Administered orally as rescue medication
Quelle: ClinicalTrials.gov
