Randomised phase III trial of ADT +/- darolutamide in frail men with castration-naïve de novo metastatic prostate cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Apr 2022 → ongoing

Decision date (initial)

2023-05-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Unicancer

External identifiers

EU CT number

2022-502425-18-00

EudraCT number

2020-003663-26

ClinicalTrials.gov

NCT04916613

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To compare the efficacy of ADT + darolutamide vs ADT + placebo in terms of radiographic progression-free survival in patients with castration-naïve de novo metastatic prostate cancer with vulnerable functional ability and not elected for docetaxel or other androgen receptor pathway inhibitors.

Secondary objectives 9

1. To assess the efficacy of ADT + darolutamide vs ADT + placebo in terms of Castration-resistant prostate cancer-free survival, Clinical progression-free survival (cPFS), Overall survival
2. To assess the safety profile of the ADT + darolutamide combination
3. Time to worsening in prostate cancer-related urinary symptoms
4. Time to next symptomatic skeletal event
5. Prostate specific antigen (PSA) response
6. Prostate cancer-specific survival
7. To assess the effect of ADT + darolutamide on subsequent lines of therapy
8. To evaluate the evolution of quality of life and geriatric status in individuals during the treatment period
9. To evaluate the impact of sarcopenia on survival and treatment response.

Conditions and MedDRA coding

Adenocarcinoma of the prostate

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Signed a written informed consent form prior to any trial specific procedures.
2. Men with histologically or cytologically confirmed adenocarcinoma of the prostate.
3. Aged ≥18 years old at the time of signing informed consent
4. De novo metastatic disease defined by clinical or radiographic evidence of metastases.
5. Measurable disease or bone lesions that are evaluable according to PCWG3 criteria
6. Ineligible for treatment with all of the following drugs: docetaxel, abiraterone, enzalutamide, apalutamide; AND meets at least one of the frailty criteria
7. Adequate bone marrow function: haemoglobin ≥80g/L, white blood cells ≥ 3.0 x109/L and platelets ≥80 x109/L.
8. Adequate liver function: alanine aminotransferase (ALT) < 2 xULN and bilirubin < 1.5 xULN, (or if bilirubin is between 1.5-2x ULN, they must have a normal conjugated bilirubin). For patients with documented liver metastasis ALT < 5 xULN is acceptable
9. Adequate renal function: calculated creatinine clearance > 30 ml/min (using the MDRD or CKD EPI method)
10. For sexually active men, agreement to use adequate contraception for the duration of trial participation and up to 2 weeks after completing study treatment
11. Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials)
12. Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.

Exclusion criteria 17

1. Three or more Grade 3, or any Grade 4 events on the CISR-G questionnaire.
2. Eastern Cooperative Oncology Group (ECOG) performance status score ≥3
3. Hypertension not controlled by an anti-hypertensive treatment (systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 95 mmHg; 3 consecutive measures taken 5 minutes apart).
4. Acute toxicities of prior treatments and procedures not resolved to grade ≤ 1 or baseline before randomisation with the exception of hot flushes and erectile dysfunction.
5. Previous systemic treatment for prostate cancer, except less than 12 weeks of ADT and/or an old-generation AR inhibitor.
6. Severe or uncontrolled concurrent disease, infection or co-morbidity.
7. Known hypersensitivity to the study treatment or any of its ingredients.
8. Major surgery within 28 days before randomisation.
9. Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV.
10. Prior malignancy ≤ 3 years before study enrolment. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any localized cancer for which treatment has been completed ≥6 months before randomisation and from which the subject has been disease-free, or for which the risk of relapse is less than 30%, as well as early stage chronic lymphocytic leukaemia that does not require any specific treatment.
11. Inability to swallow oral medications
12. Gastrointestinal disorder or procedure that can be expected to interfere significantly with the absorption of study treatment.
13. Known to have active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease at screening.
14. Treatment with any investigational product within 28 days before randomisation.
15. Concurrent participation in another clinical trial involving an investigational product (patients enrolled in non-experimental trials with no modification of the standard of care can be included).
16. Individual of full age deprived of liberty or placed under a legal protection measure (tutorship/curatorship/temporary guardianship).
17. Significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule or any condition that, in the opinion of the investigator, would preclude participation in this trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Radiographic progression-free survival, defined as time from randomisation to radiographic progression as assessed by the investigator according to PCWG3 criteria (Scher, 2016; Appendix 3), or death, whichever occurs first.

Secondary endpoints 4

1. Castration-resistant prostate cancer (CRPC)-free survival, defined as the time from randomisation to onset of CRPC according to PCWG3 criteria, or death, whichever occurs first.
2. Clinical progression-free survival, defined as time from randomisation to first occurrence
3. Overall survival, defined as the time from randomisation to the time of death from any cause. For subjects alive at the time of analysis, data will be censored on the last date the subject was known to be alive or lost to follow-up or withdraw consent.
4. Toxicity will be evaluated according to version 5 of the National Cancer Institut - Common Terminology Criteria for Adverse Events

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Director of regulatory Affairs and Pharmacovigilance

Public contact point

Organisation

Unicancer

Contact name

Director of regulatory Affairs and Pharmacovigilance

Locations

10 EU/EEA countries · 97 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 148 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

14 submissions — initial application plus substantial / non-substantial modifications