AZD5305 vs Placebo in Men With Metastatic Castration-Sensitive Prostate Cancer Receiving Physician's Choice New Hormonal Agents

Study Overview
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Brief Summary
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The intention of the study is to demonstrate superiority of AZD5305 + physician's choice NHA relative to placebo + physician's choice NHA by assessment of radiographic progression-free survival (rPFS) in participants with mCSPC.

Detailed Description
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Approximately 1800 adult participants with mCSPC will be assigned to one of two cohorts (550 HRRm and 1250 non-HRRm) and randomized in a 1:1 ratio to receive either AZD5305 with NHA or placebo with NHA. They will receive their assigned treatment and regular tumor evaluation scans until disease progression, or until treatment is stopped for another reason. All patients will be followed for survival until the end of the study. Independent data monitoring committee (DMC) composed of independent experts will be convened to confirm the safety and tolerability of AZD5305 + physicians choice NHA.

Official Title
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A Randomized, 2-cohort, Double-blind, Placebo-controlled, Phase III Study of AZD5305 in Combination With Physician's Choice New Hormonal Agents in Patients With HRRm and Non-HRRm Metastatic Castration-Sensitive Prostate Cancer (EvoPAR-Prostate01)

Conditions
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Metastatic Castration-Sensitive Prostate Cancer

Intervention / Treatment
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* Drug: AZD5305
* Drug: Placebo
* Drug: Abiraterone Acetate
* Drug: Darolutamide
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male ≥ 18 years of age Histologically documented prostate adenocarcinoma which is de novo or recurrent and castration-sensitive. Participants with pathologic features of small cell, neuroendocrine, sarcomatoid, spindle cell, or signet cell histology are not eligible. Metastatic disease as documented by the investigator prior to randomisation, with clear evidence of ≥ 1 bone lesion and/or ≥ 1 soft tissue lesion that is suitable for repeated assessment with CT and/or MRI. Participant is receiving ADT with a GnRH analogue or has undergone bilateral orchiectomy starting ≥ 14 days and < 4 months prior to randomisation ECOG performance status of 0 or 1 with no deterioration over the 2 weeks prior to randomisation. Provision of FFPE tumour tissue sample and blood sample (for ctDNA) Confirmed HRRm status by central tumour tissue and/or ctDNA test is required to determine cohort eligibility Adequate organ and bone marrow function as described in study protocol Participants must not father children or donate sperm from signing ICF, during the study intervention and for 6 months after the last dose of study intervention. Participants must use a condom from signing ICF, during study intervention, and for 6 months after the last dose of study drug, with all sexual partners. Exclusion Criteria: Participants with a history of MDS/AML or with features suggestive of MDS/AML Participants with any known predisposition to bleeding Any history of persisting (> 2 weeks) severe cytopenia Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5305 and/or the assigned NHA. History of another primary malignancy, with exceptions Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anticancer therapy. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention Cardiac criteria, including history of arrythmia and cardiovascular disease Any prior anticancer pharmacotherapy or surgery for metastatic prostate cancer, with exceptions: Prior treatment within 14 days with blood product support or growth factor support. Participants who are unevaluable for both bone and soft tissue progression

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: within each cohort (HRRm and non-HRRm), participants are randomised in 1:1 ratio to one of two treatment arms
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: AZD5305 + Physician's Choice NHA<br>AZD5305 + physician's choice NHA (Abiraterone, Darolutamide, or Enzalutamide) | Drug: AZD5305<br>* Oral<br>Drug: Abiraterone Acetate<br>* Oral<br>* Other names: Zytiga;Drug: Darolutamide<br>* Oral<br>* Other names: Nubequa;Drug: Enzalutamide<br>* Oral<br>* Other names: Xtandi;|
| Placebo Comparator: Arm 2: Placebo + Physician's Choice NHA<br>Placebo + physician's choice NHA (Abiraterone, Darolutamide, or Enzalutamide) | Drug: Placebo<br>* Oral<br>Drug: Abiraterone Acetate<br>* Oral<br>* Other names: Zytiga;Drug: Darolutamide<br>* Oral<br>* Other names: Nubequa;Drug: Enzalutamide<br>* Oral<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-Free Survival (rPFS) | rPFS is defined as the time from randomisation to radiographic progression, as assessed by the investigator per RECIST 1.1 (soft tissue) and/or PCWG3 criteria (bone), or, death due to any cause. | up to approximately 50 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomisation until the date of death due to any cause. | up to approximately 90 months | 
| Second Progression-Free Survival (PFS2) | Time from randomisation to PFS2 is defined as the time from randomisation to the earliest of progression (defined as radiographic progression, clinical progression, or PSA progression) after initiation of first subsequent treatment following the initial investigator-assessed progression or death. | up to approximately 90 months | 
| Time to First Subsequent Therapy or Death (TFST) | TFST is defined as the time from randomisation to the start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause. | up to approximately 90 months | 
| Symptomatic Skeletal Event-Free Survival (SSE-FS) | SSE-FS is defined as the time from randomisation to the earliest of the following: Use of radiation therapy to prevent or relieve skeletal symptoms. Occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral). Occurrence of spinal cord compression. Orthopaedic surgical intervention for bone metastasis. Death due to any cause. | up to approximately 90 months | 
| Time to the First Castration-Resistant Event (TTCR) | TTCR is defined as the time from randomisation to the first castration resistant event (radiographic disease progression per RECIST 1.1 [soft tissue] and/or PCWG3 criteria [bone], PSA progression per PCWG3, or SSE, PSA progression per PCWG3, or SSE), whichever occurs first, with castrate levels of testosterone (below 50 ng/dL). | up to approximately 90 months | 
| Time to Pain Progression (TTPP) | TTPP is defined as the time from randomisation to clinically meaningful pain progression based on a 2-point increase from baseline in the Brief Pain Inventory - Short Form (BPI-SF) Item 3 'worst pain in 24 hours' score and/or initiation of/increase in opioid analgesic use. | up to approximately 90 months | 
| Time To Deterioration in Urinary Symptoms (TTDUS) | TTDUS is defined as the time from randomisation to deterioration in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Prostate Questionnaire (Urinary Symptoms) (QLQPR25 [US]) subscale scores. | up to approximately 90 months | 
| Time to Deterioration in Fatigue (TTDF) | TTDF is defined as the time from randomisation to deterioration in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7A scores. | up to approximately 90 months | 
| Time to Deterioration in Physical Function (TTDPF) | TTDPF is defined as the time from randomisation to deterioration in PROMIS Physical Function Short Form 8C scores. | up to approximately 90 months | 
| Health-related Quality of Life (HrQoL) | Change from baseline in BPI-SF worst pain score, pain severity, and interference domain scores. | up to approximately 90 months | 
| BRCA and other HRR gene mutation status. |  | at screening | 
| Plasma concentrations of AZD5305 |  | up to approximately 90 months | 
| Samples will be used to develop complementary or companion diagnostics by analyzing their performance characteristics and calculate their consistency with clinical trial assays used for enrolment onto the study. | Samples will be tested by a CDx to certify consistency with assays used in the study. | up to approximately 90 months | 
| PSA (prostate-specific antigen) undetectable rate at 6, 12 months | proportion of participants with undetectable PSA (< 0.2 ng/mL) for those with PSA ≥ 0.2 ng/mL at baseline | up to approximately 90 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD5305; HRRm; non-HRRm; mCSPC; Prostate Cancer