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Trial registered on ANZCTR


Registration number
ACTRN12623000160639
Ethics application status
Approved
Date submitted
4/01/2023
Date registered
16/02/2023
Date last updated
16/02/2023
Date data sharing statement initially provided
16/02/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomized, Open-Label, Phase 2 Study of Darolutamide as Single Agent or in Combination with EPI-7386 as a Neoadjuvant Treatment for Patients Undergoing Prostatectomy for Localized Prostate Cancer (DaSCENT)
Scientific title
A Randomized, Open-Label, Phase 2 Study of Darolutamide as Single Agent or in Combination with EPI-7386 as a Neoadjuvant Treatment for Patients Undergoing Prostatectomy for Localized Prostate Cancer (DaSCENT)
Secondary ID [1] 308696 0
Nil known
Universal Trial Number (UTN)
Trial acronym
DaSCENT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate cancer 328626 0
Condition category
Condition code
Cancer 325630 325630 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients with high-risk localised prostate cancer will be treated with darolutamide alone or
daroluatmide and EPI-7386 prior to prostatectomy.

Darolutamide:
- oral tablet administration, 600mg twice daily for 12 weeks

EPI-7386:
- oral tablet administration, 300mg twice daily for 12 weeks

Prostatectomy will occur the day after completing the 12 weeks (+/- 14 days) of neoadjuvant therapy.

Patients will be given a diary to help them keep on track with taking the study tablets. The patient diary will be reviewed by the study team during and at the end of the trial. Patients will also be instructed to return all remaining drug and packaging to monitor adherence to the intervention.
Intervention code [1] 325160 0
Treatment: Drugs
Comparator / control treatment
No control group

Historical control group:
- No historical patients would have received neo-adjuvant daroluatmide or EPI.
- The intent of the de facto comparison to the historical cohorts are to provide some context for the findings. There will be other studies that have been recently published that will also assist in the interpretation, e.g. Lee et al., 2022 using more analogous drugs such as apalutamide.
- Historical comparisons are not from St Vincent's Hospital patients. Previous research on neoadjuvant therapy prior to radical prostatectomy excluding novel agents is reviewed in the protocol, with references ranging from 1995 onwards.
Control group
Historical

Outcomes
Primary outcome [1] 333481 0
Complete pathological response rate at prostatectomy following treatment with combination of EPI-7386 + Darolutamide, or Darolutamide alone for 12 weeks. Assessed on the pathological specimen obtained from prostatectomy.
Timepoint [1] 333481 0
Time of prostatectomy. - the day after completing neoadjuvant therapy.
Secondary outcome [1] 417211 0
Pathological:
To determine the effects of doublet therapy and Darolutamide alone on selected pharmacodynamic markers on prostatectomy specimens, including apoptosis, mitotic index, androgen receptor signaling, and others
Timepoint [1] 417211 0
Time of prostatectomy. - the day after completing neoadjuvant therapy.
Secondary outcome [2] 417212 0
Pathological:
Rate of positive surgical margins assessed on pathological specimen acquired at prostatectomy.
Timepoint [2] 417212 0
Time of prostatectomy. - the day after completing neoadjuvant therapy.
Secondary outcome [3] 417956 0
Pathological:
Rate of extracapsular extension assessed on pathological specimen acquired at prostatectomy.
Timepoint [3] 417956 0
Time of prostatectomy. - the day after completing neoadjuvant therapy.
Secondary outcome [4] 417957 0
Pathological:
Rate of positive seminal vesicles assessed on pathological specimen acquired at prostatectomy.
Timepoint [4] 417957 0
Time of prostatectomy. - the day after completing neoadjuvant therapy.
Secondary outcome [5] 417958 0
Pathological:
Rate of positive lymph nodes assessed on pathological specimen acquired at prostatectomy.
Timepoint [5] 417958 0
Time of prostatectomy - the day after completing neoadjuvant therapy.
Secondary outcome [6] 418327 0
Hormonal:
Effect on tissue and serum testosterone and dihydrotestosterone (DHT) for doublet therapy and Darolutamide alone.
Timepoint [6] 418327 0
Mass Spectrometry analysis of testosterone, dihydrotestosterone in tissue and blood.
Secondary outcome [7] 418328 0
Hormonal:
Intra-prostatic levels of EPI-7386 and Darolutamide.
Timepoint [7] 418328 0
Mass Spectrometry analysis of EPI-7386 and Daroluatmide.
Secondary outcome [8] 418329 0
Hormonal:
Effects on prostate-specific antigen (PSA).
Timepoint [8] 418329 0
Expression of PSA assessed by blood test.
Secondary outcome [9] 418330 0
Safety:
Safety and tolerability of doublet therapy and Darolutamide alone in the neoadjuvant setting.
Timepoint [9] 418330 0
Assessed by adverse events reported throughout the study.
Secondary outcome [10] 418331 0
Safety:
Health-related quality of life effects of doublet therapy and Darolutamide alone, focusing on toxicity.
Timepoint [10] 418331 0
Assessed by health related quality of life assessments throughout the study.
Secondary outcome [11] 418332 0
Imaging:
Effects of doublet therapy and Darolutamide alone on PSMA PET parameters such as MTV (Metabolic Tumour Volume) and SUV (Standardised Uptake Value) Max.
Timepoint [11] 418332 0
Assessed by PSMA PET at screening and at day 85.
Secondary outcome [12] 418333 0
Imaging:
Effects of doublet therapy and Darolutamide alone on MRI parameters such as PIRADS score, T2-Weighted imaging (T2WI), Diffusion-weighted Imaging (DWI), Dynamic contrast enhanced imaging (DCEI).
Timepoint [12] 418333 0
Assessed by MRI at parameters assessed at screening and at day 85.
Secondary outcome [13] 418334 0
Genomics:
Effects of doublet therapy and Darolutamide alone on the AR transciptome as measured by RNA/ Nanostring sequencing/ Single-cell sequencing.
Timepoint [13] 418334 0
Assayed by Next-generation Sequencing/ Nanostring/ Single-cell sequencing platforms
Secondary outcome [14] 418335 0
Genomics:
Effects of doublet therapy and Darolutamide alone on whole exome/ WGS tissue sequencing and correlations with ctDNA.
Timepoint [14] 418335 0
Assayed by Next-generation Sequencing of tissue and circulating tumour DNA.
Secondary outcome [15] 418336 0
Genomics:
Effects of doublet therapy and Darolutamide alone on the AR proteome.
Timepoint [15] 418336 0
Assayed by proteomic assays including quantitative immunohistochemistry, transcriptomics and mass spectrometry.

Eligibility
Key inclusion criteria
1. Willing and able to provide informed consent;
2. Men greater than or equal to 18 years of age;
3. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features with a 5 yr progression free probability of less than 80% as per the MSKCC calculator (https://www.mskcc.org/nomograms/prostate/pre_op);
4. Must be candidates for radical prostatectomy and considered surgically resectable by urologic evaluation;
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1;
6. No evidence of metastatic disease outside the pelvis as determined by radionuclide bone scans and computed tomography/magnetic resonance imaging OR PSMA-PET scan;
7. Able to swallow the study drug(s) as prescribed and comply with study requirements;
8. Archived prostate biopsy tissue sample available or willing to undergo fresh biopsy.
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Received an investigational agent within 4 weeks prior to randomization;
2. Stage T4 prostate cancer by clinical examination or radiologic evaluation;
3. Hypogonadism or severe androgen deficiency as defined by screening serum testosterone below the normal range for the institution;
4. Prior androgen deprivation, anti-androgen, chemotherapy, surgery, or radiation for prostate cancer;
5. Receiving concurrent androgens, estrogens, or progestational agents, or received any of these agents within the 6 months prior to randomization;
6. History of another malignancy within the previous 2 years other than curatively treated non-melanomatous skin cancer, superficial bladder cancer or other cancers unlikely to affect study outcomes;
7. Uncontrolled intercurrent illness, including, but not limited to, active infection or deep venous thrombosis within 3 months prior to randomization;
8. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment;
9. Unwilling to use contraceptives while on study and for 3 months after study (subjects are required to use barrier protection with sexual partners);
10. Any of the following laboratory values obtained within 14 days prior to randomization:
Absolute neutrophil count < 1500/µL, platelet count < 100,000/µL, or hemoglobin < 10 g/dL) (patients may not have received any growth factors within 7 days or blood transfusions within 28 days of the hematologic laboratory values obtained at the Screening visit)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is concealed - central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
For each arm of the study, the proportion of patients who achieve a complete or near complete (CR or nCR) pathological response will be estimated based on the following calculation: based on the A’hern phase 2 design, given a P0= 0.05, and P1 = 0.25, and alpha = 0.05 with a 80% power, then the arm will be considered a success if 3/16 patients reach a cPR or nCPR.

The primary efficacy analysis will determine the proportion of patients who achieve a complete pathological response after neoadjuvant therapy upon radical prostatectomy. For each arm of the study, the proportion of patients who achieve a complete or near complete (CR or nCR) pathological response (see section 9.5.3.1) will be estimated based on the following calculation – Based on the A’hern phase 2 design, given a P0= 0.05, and P1 = 0.25, and alpha = 0.05 with a 80% power, then the arm will be considered a success if 3/16 patients reach a cPR or nCPR. Note that arms will not be compared given the non-comparative design. Patients are randomized between 2 arms however at study entry.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/02/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
32
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 23770 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 39215 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 312924 0
Hospital
Name [1] 312924 0
St Vincent's Hospital Sydney
Country [1] 312924 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital Sydney
Address
390 Victoria Street, Darlinghurst, NSW, 2010
Country
Australia
Secondary sponsor category [1] 314604 0
None
Name [1] 314604 0
Address [1] 314604 0
Country [1] 314604 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312196 0
St Vincent's Hospital Sydney
Ethics committee address [1] 312196 0
Ethics committee country [1] 312196 0
Australia
Date submitted for ethics approval [1] 312196 0
31/10/2022
Approval date [1] 312196 0
23/11/2022
Ethics approval number [1] 312196 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123814 0
Prof Anthony Joshua
Address 123814 0
St Vincent's Hospital Sydney, Level 5, The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, NSW, 2010
Country 123814 0
Australia
Phone 123814 0
+61 293555655
Fax 123814 0
Email 123814 0
anthony.joshua@svha.org.au
Contact person for public queries
Name 123815 0
Robert Kent
Address 123815 0
St Vincent's Hospital Sydney, Level 6, The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, NSW, 2010
Country 123815 0
Australia
Phone 123815 0
+61 293555611
Fax 123815 0
Email 123815 0
robert.kent@svha.org.au
Contact person for scientific queries
Name 123816 0
Anthony Joshua
Address 123816 0
St Vincent's Hospital Sydney, Level 5, The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, NSW, 2010
Country 123816 0
Australia
Phone 123816 0
+61 293555655
Fax 123816 0
Email 123816 0
anthony.joshua@svha.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All data will be de-identified and/or used in aggregate form.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17960Ethical approval  robert.kent@svha.org.au



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.