A Randomized, 2-cohort, Double-blind, Placebo-controlled, Phase III Study of Saruparib (AZD5305) in Combination with Physician’s Choice New Hormonal Agents in Patients with HRRm and non-HRRm Metastatic Castration Sensitive Prostate Cancer (EvoPAR-Prostate01)
Trial Acronym
EvoPAR Prostate01
Secondary IDs if Any
Secondary ID
Identifier
D9723C00001_V3.0 dated 22 Sep 2023
Protocol Number
EU CT: 2023-50424-30-00
EudraCT
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Mr Sandeep AV
Designation
Senior Director, Oncology Country Head – Oncology Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park,Rachenahalli, Outer Ring Road.
Bangalore
Bangalore KARNATAKA 560045 India
Phone
9845079472
Fax
Email
sandeep.av@astrazeneca.com
Details of Contact Person Scientific Query
Name
Mr Sandeep AV
Designation
Senior Director, Oncology Country Head – Oncology Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park,Rachenahalli, Outer Ring Road.
Bangalore
KARNATAKA 560045 India
Phone
9845079472
Fax
Email
sandeep.av@astrazeneca.com
Details of Contact Person Public Query
Name
Mr Sandeep AV
Designation
Senior Director, Oncology Country Head – Oncology Site Management & Monitoring India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park,Rachenahalli, Outer Ring Road.
Bangalore
KARNATAKA 560045 India
Phone
9845079472
Fax
Email
sandeep.av@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB
151 85 Sodertalje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Södertälje Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca Pharma India Ltd
AstraZeneca Pharma India Limited,
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore Karnataka (India)- 560045
Countries of Recruitment
Australia Austria Belgium Brazil Canada Chile China Finland France Germany Hungary India Italy Japan Malaysia Netherlands Peru Poland Republic of Korea Spain Sweden Taiwan Thailand Turkey United Kingdom
Department of Medical Oncology, DRBRAIRCH, All India Institute of Medical Sciences, Ansari Nagar New Delhi- 110029 New Delhi DELHI
9013078407
batraatul85@gmail.com
Dr Deepak Koppaka
Care Hospitals
Department of Oncology
Hi Tech City, Old Mumbai Highway, Near Cyberabad
Police Commissionerate, Jayabheri Pine Valley, Hyderabad,
Telangana 500032
Hyderabad TELANGANA
9052289998
drdeepak.koppaka@gmail.com
Dr B J Srinivas
Health care global enterprises Ltd
Department of Oncology
8 HCG towers P Kalinga Rao Road Sampangiram Nagar Bangalore 560027 Bangalore KARNATAKA
9739576694
sripav77@gmail.com
Dr Santhosh Vandanasetti
Kailash Cancer Hospital and research Centre
Department of Oncology
Muni Seva Ashram, Goraj
Waghodia,Vadodara 391760, Gujarat
Vadodara GUJARAT
9427423693
vandanasetti.santhosh@greenashram.org
Dr Saurabh Rajeshwar
KIMS Kingsway Hospitals
Department of Oncology
44, Parwana Bhawan, Kinsgway, Nagpur
440001 Maharashtra
Nagpur MAHARASHTRA
7066580511
drsaurabhprasad@gmail.com
Dr Akhil Kapoor
Mahamana Pandit,Madan Mohan Malviya Cancer Centre
Department of Oncology
A unit of Department of Atomic Energy Govt of India Sundar Bagiya , Near Nariya Gate Banaras Hindu University Campus Varanasi – 221005 Uttar Pradesh Varanasi UTTAR PRADESH
9950482121
kapoorakhil1987@gmail.com
Dr Sreedharan P S
MVR Cancer Centre and Research Institute
Department of Oncology
CP13516 B.C Vellalasseri, NIT 9Via Poolacode, Kozhikode 673601 Kozhikode KERALA
9496286696
drsreedharan@mvrccri.co
Dr Chandrakanth MV
NH-Rabindranath Tagore International Institute of Cardiac Sciences
Department of Oncology
Premised No 1489 124, Mukundapur, E M Bypass,PIN 700099.
West Bengal
Kolkata WEST BENGAL
7003206633
drmvch@gmail.com
Dr Amitabh Singh
Rajiv Gandhi Cancer Institute and Research Centre
Department of Oncology
Sir Chotu Ram Marg, Sector-5 Rohini, New Delhi - 110085 New Delhi DELHI
9643710442
amitabhsingh27@gmail.com
Dr Vikas T Talreja
Regency Hospital
Department of Oncology
A 4 Sarvodaya
Nagar, Kanpur
208005, UP
Kanpur Nagar UTTAR PRADESH
9702288801
vikasttalreja@gmail.com
Dr Tushar Patil
Sahyadri Super Speciality Hospital
Department of Oncology
30 C Erandawane Karve Road,
Pune 411004 Maharashtra India
Pune MAHARASHTRA
Control Arm:
Placebo to AZD5305 (60 mg once daily, orally + physician’s choice NHA (once daily, orally) 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
Intervention
Experimental Arm: both HRRm cohort and non HRRm Cohort
Saruparib mg + physician’s choice NHA: during the treatment period, participants will receive Saruparib 60 mg orally once daily in combination with physician’s choice NHA in cycles of 28 days.
In both cohorts, participants will be randomised in a 1:1 ratio to one of the following intervention groups:
Saruparib 60 mg + physician’s choice NHA: during the treatment period, participants will receive Saruparib 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
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.
4 ECOG performance status of 0 or 1 with no deterioration over the 2 weeks prior to randomisation.
5 Minimum life expectancy of 6 months.
6 Type of Participant and Disease Characteristics:
7. Provision of a FFPE tumour tissue sample and a blood sample (for ctDNA) as specified in the Laboratory Manual and designated Diagnostic Testing Manuals (refer to Section 8.8 and to Table 5).
8. B. Participants will be considered eligible for the Non-HRRm Cohort if no gene mutation (in any of BRCA1, BRCA2, ATM, CDK12, PALB2, RAD51B, RAD51C, RAD51D, and BARD1) is detected in tumor tissue and ctDNA test and a participant must have a non-HRRm tumour tissue test result. Participants without both a valid non-HRRm tumour tissue and ctDNA are not eligible for randomisation into the Non-HRRm Cohort. For details see Table 5 .
ExclusionCriteria
Details
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.
8 Any of the following cardiac criteria:
Mean resting corrected QT interval QTcF 470 milliseconds obtained from triplicate ECGs and averaged, recorded 5 minutes apart.
Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
9 History of arrhythmia multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, which is symptomatic or requires treatment CTCAE Grade 3, symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the AstraZeneca study physician
10 Other cardiovascular disease as defined by any of the following:
Symptomatic heart failure as defined by New York Heart Association class 2.
Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention or coronary artery bypass grafting within 6 months prior to randomisation.
Cardiomyopathy of any aetiology
Presence of clinically significant valvular heart disease.
Left ventricular ejection fraction 50% measured by echocardiogram or MUGA scan at screening or based on assessment performed within 6 months prior to randomisation.
Transient ischaemic attack, or stroke within 6 months prior to randomisation.
Participants with symptomatic hypotension at screening.
Uncontrolled hypertension despite medical management.
11 Evidence of active and uncontrolled hepatitis B and/or hepatitis C. Screening for hepatitis B and hepatitis C is not required. Participants previously exposed to hepatitis B or hepatitis C are eligible if they meet one of the following criteria:
a Are negative for HBsAg and anti-HBc or
b Are HBsAg and anti-HBc chronic hepatitis B, and meet conditions i to iii below:
HBV DNA viral load 2000 IU L.
Have normal aminotransferase values, or, if liver metastases are present, abnormal aminotransferase, with a result of AST, ALT 3 ULN, which are not attributable to HBV infection.
Start antiviral treatment at least 2 weeks prior to the first dose of study intervention and maintain antiviral treatment during the interventional period. For permitted concomitant therapies, refer to Appendix I.
c Are anti-HBc positive, HBsAg negative, and have HBV DNA 2000 IU L.
d Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
NOTE: Inclusion of this group of participants should be carefully considered if participant has no access to hepatology service and/or is currently in need of antiviral treatments.
12. Evidence of active and uncontrolled HIV infection. Participants with controlled HIV need to meet the following criteria: undetectable viral RNA load less than 400 copies mL in the last 4 weeks prior to first dose of study intervention, CD4 count of 350 cells µL, no history of AIDS defining opportunistic infection within the past 12 months, and stable on the same anti-HIV medications as permitted in Appendix I for at least 6 months. Screening for HIV is not required.
13. Active tuberculosis infection clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice.
14. Major surgical procedure excluding placement of vascular access or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. Participants should have fully recovered from any clinically significant AEs.
15. As judged by the investigator, any other evidence of diseases, such as severe or uncontrolled systemic diseases or active uncontrolled infections, including but not limited to uncontrolled major seizure disorder, active bleeding diseases, superior vena cava syndrome, or history of allogenic organ transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or would jeopardise compliance with the protocol.
16 Any prior treatment with a PARP inhibitor or platinum chemotherapy.
17 Any prior treatment with a GnRH analogue or NHA. The following exceptions are permitted:
4 months ADT for metastatic disease per inclusion criterion 4.
For localised disease and so long as there was 12 months between completion of therapy and subsequent recurrence:
ADT for a maximum of 39 months note: for injectable depot preparations of ADT, completion of therapy is defined as last dose plus one times the dosing interval eg, 12 weeks for goserelin 10.8 mg.
NHA for a maximum of 30 months.
18 Any prior anticancer pharmacotherapy including but not limited to chemotherapy, immunotherapy, and systemic radiopharmaceuticals or surgery for metastatic prostate cancer.
The following exceptions are permitted:
4 months ADT for metastatic disease per inclusion criterion 4.
Radiation therapy for example radiation therapy to the prostate for participants with low volume metastatic disease or palliative radiation therapy to treat symptoms resulting from metastatic disease. Radiation therapy needs to have been completed 4 weeks prior to randomisation for wide field radiation therapy and 2 weeks for limited field radiation therapy. Participants should have fully recovered from any clinically significant adverse events.
Surgical therapy to treat symptoms from metastatic disease if it was completed at least 4 weeks prior to first day of dosing and participant fully recovered from any clinically significant AEs.
19 Prior treatment within 14 days with blood product support or growth factor support.
20. Initiation of treatment with a bisphosphonate or denosumab for the management of bone metastasis 28 days prior to randomisation. Participants should be either on a stable dose of such agents for 28 days prior to randomisation or agree not to initiate such therapy until radiographic progression is documented. Bisphosphonates and denosumab at doses for prevention of osteoporosis are allowed.
21. Concomitant use of the following types of medications or herbal supplements within 21 days or at least 5 half-lives (whichever is longer), of randomisation:
Strong inducers and inhibitors of CYP3A4 (applies to Saruparib and all NHAs) –
Strong CYP2C8 inhibitors or inducers (applicable only to enzalutamide combination)
Strong P-glycoprotein inducers (applicable only to darolutamide combination)
29. Participants with any contraindication or restriction based on the local prescribing information that would prohibit the use of the intended physician’s choice NHA, including:
Serum potassium 3.5 mmol/L
30. Participants in whom the standard of care is judged by the investigator to be docetaxel in combination with darolutamide.
To demonstrate superiority of Saruparib + physician’s choice NHA relative to placebo + physician’s choice NHA by assessment of radiographic progression-free survival
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
The analysis will include all randomised participants in the relevant subpopulation/cohort as randomised. All events will be included regardless of whether the participant withdraws from therapy, receives another anticancer therapy, or clinically progresses prior to RECIST 1.1 (soft tissue) and/or PCWG3 criteria (bone).
To demonstrate superiority of Saruparib + physician’s choice NHA relative to placebo + physician’s 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 superiority of Saruparib + physician’s choice NHA relative to placebo + physician’s choice NHA by assessment of overall survival (OS) 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
Use of radiation therapy to prevent or relieve skeletal symptoms.Occurrence of new symptomatic pathological bone fractures vertebral or non vertebral. Radiographic documentation is required. A pathological fracture, as determined by investigator, is defined as associated with low or no trauma and deemed to have occurred at a site of bone metastasis
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.
The analysis will include all randomised participants in the relevant subpopulation cohort as randomised.
The measure of interest is the change from baseline in BPI SF worst pain item and domain pain 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 Saruparib + physician’s choice NHA relative to placebo + physician’s 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 & defined according to local standard clinical practice.
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:
TEAEs, SAEs, AEs leading to dose modifications.Changes from baseline in vital signs, clinical laboratory assessments, electrocardiograms, and physical examinations
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:
• The investigator
• BICR
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
Prostate cancer 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
This may include but is not limited to:
Assessment of association of biomarkers including HRRm status, genetic and epigenetic alterations, mRNA, proteins, RAD51 foci, and immune markers with observed response and/or resistance to AZD5305
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:
Analysis of tumour specific and circulating biomarkers, such as tumour DNA, genes genetic variations, mRNA, proteins, cytokines, or metabolites.Pharmacogenomics Genomics Initiative.
Samples or derivatives may be used to evaluate or develop potential future diagnostic tests by AstraZeneca or its partners.
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:
• rPFS as determined by PSMA-PET
• Early response as determined by PSMA-PET vs rPFS
• rPFS as determined by conventional imaging vs rPFS as determined by PSMA-PET
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))
Radiographic progression-free survival (rPFS) in participants with mCSPC.
RECIST 1.1 is to be assessment at screening, & 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
Assessment of overall survival (OS) in participants with mCSPC.
(BRCAm, Non HRRm & HRRm cohort)
The analysis will include all randomised participants in the relevant subpopulation/cohort as randomised. All deaths will be included regardless of whether the participant withdraws from therapy or receives another anticancer therapy.
OS is defined as the time from randomisation until the date of death due to any cause.
The measure of interest is the HR of OS
Target Sample Size
Total Sample Size="1800" Sample Size from India="70" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
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 Saruparib + 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.
In both cohorts, participants will be randomised in a 1:1 ratio to one of the following intervention groups:
Saruparib 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 Saruparib /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.