A Randomized, 2 cohort, Double blind, Placebo controlled, Phase III Study of AZD5305 in Combination with Physicians Choice New Hormonal Agents in Patients with HRRm and non HRRm Metastatic Castration Sensitive Prostate Cancer EvoPAR Prostate01
Overview
- Phase
- Phase 3
- Status
- Recruiting
- Sponsor
- AstraZeneca AB
- Enrollment
- 1,800
- Locations
- 12
- Primary Endpoint
- (BRCAm and Non HRRm cohort)
Overview
Brief Summary
This is a Phase III, 2-cohort, 2-arm, parallel-group, randomised, double-blind, placebo-controlled, multicentre, global study, assessing the efficacy and safety of AZD5305 + physician’s choice New hormonal agent (NHA ) compared with placebo + physician’s choice NHA in participants with Metastatic castration-sensitive prostate cancer (mCSPC) with and without Homologous recombination repair (mutation).Study details include:
· The study duration will be up to 90 months.
Study Cohorts, Arms, and Duration:
The study will have 4 periods: HRRm testing, screening, treatment, and follow-up:
• Potential participants will undergo prospective central HRRm testing, which may occur prior to the main screening period based on a separate informed consent (HRRm testing informed consent form). Local HRRm results will not be acceptable. HRRm testing must be completed and have a known result prior to randomisation. Participants will be allocated to 1 of the 2 cohorts (HRRm or Non-HRRm) prior to randomisation to study intervention based on the result of central HRRm testing. Treatment with ADT can be commenced while awaiting HRRm test results, as long as participants are randomised within 14 days to 4 months after start of ADT and no evidence of disease progression is found. It is recommended that results from HRRm testing are available prior to screening, however if necessary HRRm testing and the screening period can be performed in parallel.
• The screening period will commence once consent is obtained for the main study and will be up to 28 days.
· In both cohorts, participants will be randomised in a 1:1 ratio to one of the following intervention groups:
− AZD5305 60 mg + physician’s choice NHA: during the treatment period, participants will receive AZD5305 60 mg orally once daily in combination with physician’s choice NHA in cycles of 28 days.
− Placebo + physician’s choice NHA: during the treatment period, participants will receive placebo orally once daily in combination with physician’s choice NHA in cycles of 28 days.
· Physician’s choice NHA includes:
− 1000 mg abiraterone orally once daily with 5 mg prednisolone or prednisone, or
· 600 mg darolutamide orally twice daily, or
− 160 mg enzalutamide orally once daily
Randomised participants will continue treatment with AZD5305/placebo in combination with physician’s choice NHA until investigator-assessed disease progression by RECIST (Response Evaluation Criteria in Solid Tumours) version 1.1 (soft tissue lesions) and/or Prostate Cancer Working Group 3 (PCWG3) (bone lesions), unacceptable toxicity occurs, or the participant withdraws consent. The on-treatment visit frequency will be weekly to Q4W
• The treatment period will continue until investigator-assessed disease progression by RECIST 1.1 and/or PCWG3 progression criteria, unacceptable toxicity occurs, or the participant withdraws consent.
• The follow-up period will start after study intervention discontinuation (ie, after both AZD5305/placebo and NHA have been discontinued).
Follow-up of Participants Post Discontinuation of Study Intervention:
After study intervention discontinuation, all participants will undergo a treatment discontinuation visit (within 7 days of discontinuation) and will be followed up for safety assessments 30 days after their last dose of study intervention (ie, the safety follow-up visit).
Participants who have discontinued study intervention in the absence of RECIST 1.1 or. PCWG3-defined radiographic progression by investigator assessment will be followed up with tumour assessments according to the Schedule of Activities (SoA) until investigator-assessed RECIST 1.1 and/or PCWG3-defined disease progression or death, regardless of whether or not the participant started a subsequent anticancer therapy, unless they have withdrawn consent to all study-related assessments.
In addition, after the study intervention discontinuation and safety follow-up visit all participants will be followed up for survival status after study intervention discontinuation every 16 weeks (± 14 days) until death, withdrawal of consent, or the data cut-off (DCO) for the final analysis, whichever comes first, as per the schedule of assessment . Long-term survival follow-up data may be collected in the electronic data capture system for up to approximately 2 years after the final formal overall survival (OS) analysis DCO, to allow further exploratory analysis of OS. Participants who discontinue treatment and are in long-term follow-up (after final analysis DCO) should continue survival assessments every 16 weeks during the long-term survival follow-up.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Masking
- Participant and Investigator Blinded
Eligibility Criteria
- Ages
- 18.00 Year(s) to 99.00 Year(s) (—)
- Sex
- Male
Inclusion Criteria
- •Inclusion criteria Type of Participant and Disease Characteristics 1 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.
- •2 Metastatic disease as documented by the investigator prior to randomisation, with clear evidence of 1 bone lesion (defined as one lesion with positive uptake on bone scan) and/or 1 soft tissue lesion (measurable and/or non-measurable) that can be accurately assessed at baseline and is suitable for repeated assessment with CT and/or MRI.
- •Participants with metastatic disease identified by PSMA-PET only, will not be eligible.
- •Participants with disease limited to regional pelvic lymph nodes only are not eligible.
- •3 Participant is receiving ADT with a GnRH analogue or has undergone bilateral orchiectomy starting 14 days and 4 months prior to randomisation with no radiographic evidence of disease progression or rising PSA levels prior to first day of dosing.
- •Participant must remain on ADT throughout the study and be a candidate for treatment with an NHA.
- •Combination with first generation AR antagonists to counter testosterone flare is permitted until randomisation.
- •Note: Due to the interaction between relugolix and enzalutamide, this combination of ADT and NHA is not allowed.
- •Relugolix is otherwise permitted.
Exclusion Criteria
- •Exclusion criteria Medical Conditions 1 Participants with a history of MDS AML or with features suggestive of MDS AML as determined by prior diagnostic investigation.
- •Specific screening for MDS AML is not required.
- •2 Participants with any known predisposition to bleeding eg, active peptic ulceration, recent within 6 months haemorrhagic stroke, proliferative diabetic retinopathy.
- •3 Any history of persisting 2 weeks severe cytopenia due to any cause eg, absolute neutrophil count 0.5 109 L or platelets 50 109 L 4 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.
- •5 History of another primary malignancy, with the following exceptions: Adequately resected non-melanoma skin cancer.
- •Curatively treated in situ disease.
- •Malignancy treated with curative intent 3 years before the first dose of study intervention, and with no known active disease during the intervening time period.
- •6 Persistent toxicities CTCAE Grade 2 caused by previous anticancer therapy.
- •Participants with side effects that are not reasonably expected to affect the safety of the participant on study intervention in the opinion of the investigator eg, ADT-related side effects may be included if agreed with the Study Clinical Lead 7 Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.
- •A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and signing the main study ICF.
Outcomes
Primary Outcomes
(BRCAm and Non HRRm cohort)
Time Frame: RECIST 1.1 is to be assessment at screening, and Every 16 weeks (± 14 days) from randomisation until RECIST 1.1 and/or PCWG3-defined radiographic PD. | 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.
Radiographic progression-free survival (rPFS) in participants with mCSPC
Time Frame: RECIST 1.1 is to be assessment at screening, and Every 16 weeks (± 14 days) from randomisation until RECIST 1.1 and/or PCWG3-defined radiographic PD. | 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.
Secondary Outcomes
- To demonstrate superiority of AZD5305 physician s choice NHA relative to placebo physicians choice NHA by assessment of radiographic progression-free survival rPFS in participants with mCSPC(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.)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of time to first subsequent therapy or death TFST in participants with mCSPC(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.The analysis will include all randomised participants in the relevant subpopulation cohort as randomised. All events will be included, regardless of progression status.The measure of interest is the HR of TFST)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of symptomatic skeletal event free survival SSEF S in participants with mCSPC(SSE FS is defined as the time from randomisation to the earliest of the following)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of time to the first castration resistant event TTCR in participants with mCSPC(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.The analysis will include all randomised participants in the relevant subpopulation cohort as randomised. All events will be included, regardless of progression status)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of time to pain progression TTPP in participants with mCSPC(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.The analysis will include all randomised participants in the relevant subpopulation cohort as randomised. All events will be included, regardless of progression status.The measure of interest is the HR of TTPP)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of time to deterioration in urinary symptoms TTDUS in participants with mCSPC(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 QLQ PR25 US subscale scores.The analysis will include all randomised participants in the relevant subpopulationcohort as randomised. All events will be included, regardless of progression status.The measure of interest is the HR of TTDUS)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of time to deterioration in fatigue TTDF in participants with mCSPC(TTDF is defined as the time from randomisation to deterioration in Patient Reported Outcomes Measurement Information System PROMIS Fatigue Short Form 7A scores.The analysis will include all randomised participants in the relevant subpopulation cohort as randomised. All events will be included, regardless of progression status.The measure of interest is the HR of TTDF)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of time to deterioration in physical function TTDPF in participants with mCSPC(TTDPF is defined as the time from randomisation to deterioration in PROMIS Physical Function Short Form 8C scores.The analysis will include all randomised participants in the relevant subpopulation cohort as randomised. All events will be included, regardless of progression status.The measure of interest is the HR of TTDPF)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of health-related quality of life HrQoL using the BPI SF in participants with mCSPC(Change from baseline in BPI SF worst pain score, pain severity, and interference domain scores.)
- To evaluate tumour and blood samples collected from participants with mCSPC for mutations in BRCA and other HRR genes.(BRCA and other HRR gene mutation status.)
- To assess the PK of AZD5305 in plasma following single and multiple dosing, and explore the relationship between the PK concentration parameters and selected endpoints which may include pharmacodynamic parameters, efficacy, and or safety.(Plasma concentrations of AZD5305 parent and metabolites if applicable, and plasma PK parameters, including but not limited to AUC, Cmax, and Tmax, as data allow. Correlation of PK with other primary secondary exploratory endpoints in participants treated with AZD5305.)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of second progression free survival PFS2 in participants with mCSPC(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. The date of second progression will be recorded by the investigator in the eCRF and defined according to local standard clinical practice.)
- To demonstrate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of time to first subsequent therapy or death TFST in participants with mCSPC(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.The analysis will include all randomised participants in the relevant subpopulation/cohort as randomised. All events will be included, regardless of progression status.The measure of interest is the HR of TFST)
- To assess the safety and tolerability of AZD5305 physicians choice NHA as compared with placebo physicians choice NHA in participants with mCSPC(Safety endpoints will include, but are not limited to, the following:)
- To estimate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of objective response rate ORR in participants with mCSPC(ORR is defined as the proportion of participants with measurable soft tissue disease who have a CR or PR per RECIST 1.1 soft tissue and PCWG3 criteria bone, as determined by:)
- To estimate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of duration of response DoR in participants with mCSPC(DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 soft tissue and or PCWG3 criteria bone as assessed by the investigator or death due to any cause)
- To estimate the effectiveness of AZD5305 physicians choice NHA relative to placebo physicians choice NHA by assessment of PSA in participants with mCSPC(Time to PSA progression, defined as the time from randomisation to PSA progression per PCWG3 criteria.PSA50 PSA90 response: proportion of participants achieving a 50%/90% decrease in PSA from baseline. PSA undetectable rate at landmark timepoints eg, 6, 12 months proportion of participants with undetectable PSA 0.2 ng mL for those with PSA 0.2 ng mL at baseline.)
- To explore the efficacy of AZD5305 physicians choice NHA relative to placebo(physicians choice NHA in terms of prostate cancer specific mortality)
- To evaluate the effects of study intervention on ctDNA(May include but is not limited to assessment of changes from baseline in ctDNA and)
- To further evaluate predictive biomarkers of clinical benefit, mechanism of action and acquired resistance to AZD5305 in combination with an NHA which may be observed using:(Blood samples, tumour samples and ctDNA)
- To develop companion or complementary diagnostic(Collected samples (including derivatives) and data will be used to develop companion or complementary diagnostic for use with AZD5305)
- Future exploratory research into factors that may influence development of cancer and/or response to treatment, may be performed on the collected and stored archival tumour samples, blood samples and their derivatives(This may include:)
- To explore how genetic variations may affect clinical parameters, risk and prognosis of diseases and the response to medications. Note: the sample is taken from consented participants for DNA isolation and storage. Results will not be reported in the CSR(Exploratory endpoints are related to the data generated from the genetic analysis of part or all of the participant’s genetic information)
- To explore PSMA-PET imaging as a biomarker in participants with mCSPC(Investigation of changes in PSMA-PET parameters, including tumour SUVmax, SUVmean to determine endpoints including but not limited to:)
- To estimate the effectiveness of AZD5305 + physician’s choice NHA relative to placebo + physician’s choice NHA by assessment of patient-reported global impression of overall severity and treatment tolerability in participants with mCSPC(Proportion of participants reporting different levels of global impression of the severity of overall cancer symptoms and overall treatment tolerability as measured by PGI-S and the PGI-TT)
- To estimate the effectiveness of AZD5305 + physician’s choice NHA relative to placebo + physician’s choice NHA by assessment of patient-reported symptoms, treatment-related AEs, functioning and global health status (GHS) using the EORTC QLQ-QL2, EORTC QLQ-PR 25(US) (4 items), and 8 key items from the EORTC IL in participants with mCSPC(Change from baseline to post-baseline in key mCSPC symptoms and in GHS/quality of life (QoL) (EORTC QLQ QL2) as well as EORTC QLQ-PR 25(US) scores and 9 key items from EORTC IL.)
- To explore the impact of treatment and disease on health state in participants with mCSPC(Dimension response and visual analogue scale over time as captured by the EQ-5D-5L)
- To explore the impact of treatment and disease on health care resource use in participants with mCSPC(Number and type of hospitalisations and procedures, and length of stay, as captured by the Concomitant Procedure, SAE reporting forms and HOSPAD)
- To explore the use of a Computer Adaptive Testing (CAT) delivered measure of Physical Function in participants with mCSPC.(Comparison of compliance, reliability, and measurement error rates of a streamlined and tailored version of physical function, based on PROMIS PF CAT scores, to the corresponding PROMIS 8C values)
- (HRRm cohort))
- Assessment of overall survival (OS) in participants with mCSPC.
Investigators
Mr Sandeep AV
AstraZeneca Pharma India Ltd