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Prostatic Neoplasms

Genital Neoplasms, Male

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Genital Diseases, Male

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Male Urogenital Diseases

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Niraparib

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LHRHa plus apalutamide plus abiraterone acetate plus prednisone.

LHRHa plus abiraterone acetate plus prednisone.

LHRHa plus abiraterone acetate plus prednisone plus docetaxel.

LHRHa plus abiraterone acetate plus prednisone plus niraparib

4 tablets by mouth once a day for 24 weeks

Apalutamide 60mg Tab

4 tablets by mouth on an empty stomach once a day for 16 weeks

Abiraterone Acetate 250mg

1 tablet by mouth once daily while taking abiraterone acetate

Prednisone 5mg Tab

Infusion every 3 weeks for 6 cycles (each cycle has 3 weeks)

3 capsules by mouth once daily for 16 weeks

Niraparib 100mg Oral Capsule

1200mg infusion every 3 weeks for 6 cycles

Martin E Gleave, MD

Miran Kenk, PhD

Anthony Martinez

Marc Dall'Era, MD

Mamta Parikh, MD

Daniella Furtado

Adam Kibel, MD

Lindsay Sazkaly

Todd Morgan, MD

askMDAnderson

Brian Chapin, M.D.

Jonathan Ma

Pascale Juneau

Rodney Breau, MD

Anuja Parikh, HBSc

Neil Fleshner, M.D.

The objective of this study is to see if providing an appropriate therapy based on the genomic testing of prostate tumour tissue will result in an improved clinical response.

Each participant will be treated with 8 weeks of a luteinizing hormone-releasing hormone agonist (LHRHa) plus apalutamide (APA) while genome sequence characterization is being done. Participants with biopsy specimens deemed unevaluable for genomic testing will remain on LHRHa plus APA for an additional 16 weeks.

Participants with evaluable tissue will be assigned to one of the open-label sub-studies on the basis of genomic profiling results. Within each group, they will be randomized to a specific treatment arm either LHRHa plus APA alone or adding abiraterone acetate and prednisone, docetaxel or niraparib.

The study will evaluate the response rate and outcomes after radical prostatectomy in each arm of the trial.

This is a multi-centre adaptive multi-arm phase II study. Participants are treated with an induction period of at least 8 weeks of LHRH agonist/antagonist (LHRHa) plus apalutamide (APA) while genome sequence characterization is being done.

Genomic sequencing analysis will be performed centrally by Tempus, a CLIA (Clinical Laboratory Improvement Amendments)-certified laboratory. For the DNA gene profiling, formalin-fixed paraffin-embedded (FFPE) prostate cancer and surrounding healthy tissue from diagnostic biopsies will be used for genetic analysis. Copy number profiling will be performed using array Comparative Genomic Hybridisation (aCGH). Targeted sequencing using MiSeq (Illumina) and Ion Proton (Life Technologies) platforms will be performed to identify mutations in a panel of 648 genes.

Based on previous studies, we conservatively expect up to 25% of unevaluable needle biopsy specimens with inadequate/insufficient tumor tissue for genome sequencing. The patients with unevaluable tissue will continue on the master protocol (LHRHa + APA) for an additional 16 weeks followed by radical prostatectomy.

The genomically evaluable patients will be assigned to a specific sub-protocol according to the results of the genomic profile and randomized to a treatment arm within the sub-protocol for 16 weeks, with additional inclusion and exclusion criteria specified in dedicated sub-protocols. Radical prostatectomy will follow sub-protocol treatment.

Sub-protocol 1 - AR axis: No targetable actionable aberration; presence of TMPRSS2-ERG fusion, CHD1 loss or SPOP mutations: (\~50% expected prevalence in study population) randomized to:

1. LHRHa + APA for 16 weeks or
2. LHRHa + APA + AAP (Abiraterone Acetate + Prednisone) for 16 weeks

Sub-protocol 2 - Loss of tumour suppressor genes - PTEN, TP53 or TB loss (\~40%, bad prognosis) randomized to:

1. LHRHa + AAP for 16 weeks or
2. LHRHa + AAP + docetaxel for 6 cycles

Sub-protocol 3 - DNA damage response alterations (e.g. BRCA1/2, ATM, FANCONI, CDK12) in 6-8% assigned to:

* LHRHa + AAP + PARP (Poly \[ADP-ribose\] polymerase) inhibitors (niraparib) for 16 weeks

Sub-protocol 4 - Hypermutation, microsatellite instability (MSI), Lynch syndrome or CDK12 in less than 5% assigned to:

a. LHRHa + APA plus PD-L1 inhibitor (atezolizumab) for 16 weeks

Genomic Biomarker-Selected Umbrella Neoadjuvant Study for High Risk Localized Prostate Cancer

Pathological Minimal Residual Disease (pMRD): pathological minimal residual disease (pMRD) is defined as residual tumour 5mm or less.

Pathological minimal residual disease is defined as residual tumour 5 mm or less.

The Brief Pain Inventory-Short Form (BPI-SF) is a 9-item, self administered questionnaire which evaluates the severity of a participant's level of pain and impact on daily functioning. This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks), as well as the End of Treatment (EoT) visit.

The EQ-5D-5L is a widely used instrument developed in Europe to evaluate the generic quality of life. The EQ-5D-5L has two components: the EQ-5D descriptive system and the EQ visual analogue scale. This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks) as well as at the EoT visit.

This will be measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. The FACT-P is a multidimensional, self-report QoL instrument specifically designed for use with patients who have prostate cancer. This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks) as well as at the EoT visit.

Janssen Inc.

University Health Network, Toronto

University of British Columbia

Principal Investigator/Study Chair

Abiraterone Acetate 1000mg will be administered orally once daily

Prednisone 5mg will be administered orally twice daily with Abiraterone Acetate 1000mg

Prednisone 5mg will be administered orally twice daily with DST-2970 for 28 days after dosing of Abiraterone Acetate is stopped

Prednisone 5Mg Tab

DST-2970 will be administered orally twice daily for 28 days (for every cycle) after dosing of Abiraterone Acetate is stopped

DST-2970 (Abiraterone)

This is a Phase I multi-center, open-label, study of DST-2970 to determine the MTD, overall safety/tolerability, PK/pharmacodynamic parameters, and efficacy in prostate cancer patients.The study will include a dose escalation phase followed by a dose expansion phase. Each cohort will consist of a "run-in" period to assess pharmacokinetic trough, as well as C1hour, C2hour, and C3hour levels of standard of care abiraterone acetate, followed by a minimum of an 80-hour washout (treatment delay), then initiation of treatment with DST-2970.

The patient population that will be evaluated in this study include patients with castration sensitive or castration resistant prostate cancer who experience a rising PSA, with or without radiographic progression, while taking abiraterone acetate.

In this protocol, "initial PSA response to abiraterone" is defined as having a ≥ 30% drop in PSA levels (confirmed by a second PSA level one month later) during the first 6 months of treatment with abiraterone. These patients who subsequently experience a rise in PSA while on abiraterone are considered as having "acquired resistance" to abiraterone in the context of this protocol. Patients not meeting the definition of having an "initial PSA response to abiraterone" are considered as having "primary resistance" to abiraterone in the context of the protocol.

In the dose escalation phase, all patients with a rising PSA can be enrolled, whether they had an "initial PSA response to abiraterone" or never responded to abiraterone.

Two expansion cohorts will be opened. One expansion cohort will evaluate patients who did achieve an "initial PSA response to abiraterone" within the first 6 months of treatment as defined above, but subsequently progressed by PSA with or without radiographic progression. A second expansion cohort will evaluate patients who did not achieve an "initial PSA response to abiraterone" as defined above but have PSA progression with or without radiographic progression.

The rationale of the study is to determine if the better bioavailability of DST-2970 will overcome resistance to abiraterone acetate experienced in these two clinical settings.

In all cohorts, treatment will continue until progressive disease, unacceptable toxicity, investigator and/or sponsor decision, intercurrent illness or patient withdrawal of consent.

Patients will be monitored regularly with physical examination and laboratory tests.

PK and Dose Escalation and Expansion Study of DST-2970

A Phase 1 PK and Dose Escalation and Expansion Study of DST-2970 in Patients With Prostate Cancer With Rising PSA on Treatment With Abiraterone Acetate

To explore potential biomarkers, including germline SNPs that may help predict response to DST-2970

To evaluate the pharmacokinetic trough, as well as C1hour, C2hour, and C3hour levels of abiraterone following daily oral administration of DST-2970 to inform the dose selected for expansion in patients with prostate cancer

To measure the effectiveness of DST-2970 using CT scan results as measured by modified RECIST 1.1

To measure efficacy of DST-2970 using the blood marker PSA results

To measure type of response (e.g., CR, PR, SD)

To measure Time to Progression (rTTP) by PCWG3-modified RECIST v1.1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Genomic Biomarker-Selected Umbrella Neoadjuvant Study for High Risk Localized Prostate Cancer	NCT04812366	Prostate Cancer	Apalutamide 60m... Abiraterone Ace... Prednisone 5mg ... Docetaxel Niraparib 100mg... Atezolizumab	18 Years -	University of British Columbia
PK and Dose Escalation and Expansion Study of DST-2970	NCT04291664	Prostate Cancer	Abiraterone Ace... Prednisone 5Mg ... DST-2970 (Abira...	18 Years -	DisperSol Technologies, LLC
Genomic Biomarker-Selected Umbrella Neoadjuvant Study for High Risk Localized Prostate Cancer	NCT04812366	Prostate Cancer	Apalutamide 60m... Abiraterone Ace... Prednisone 5mg ... Docetaxel Niraparib 100mg... Atezolizumab	18 Years -	University of British Columbia

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