Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Hormones

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Degarelix

Simon C Pacey, MRCP, Ph.D

Despite recent advances in the treatment of Castrate-Resistant Prostate Cancer (CRPC), there remains an unmet medical need to identify and optimise additional treatment for those patients with early prostate cancer who are at greatest risk of relapse following first-line treatment with curative intent.

This is a phase I study investigating the feasibility and tolerability of a short course of neoadjuvant treatment with olaparib, either as a monotherapy or in combination with degarelix) given in the window-of-opportunity prior to radical prostatectomy in men with early, localised intermediate-/high- risk prostate cancer. Our primary objective is to determine the pharmacodynamic biomarker effects of olaparib (a PARP inhibitor) in this patient population.

Participants will receive either single agent olaparib or olaparib in combination with degarelix (androgen deprivation) for two weeks prior to routine radical prostatectomy. We will use immunohistochemistry to quantify changes in the levels of biomarkers of PARP inhibition, e.g. PAR, gamma H2AX, pH2A(s129) and Rad51 foci, using tumour samples taken at baseline and at the time of radical prostatectomy. An intra-operative prostate biopsy will permit us to examine biomarker variability between the samples.

The incidence and severity of Adverse Events will be documented and we will assess the number of trial participants who undergo surgery on schedule. We will assess preliminary evidence of tumour response, e.g. pathological changes and Prostate Specific Antigen (PSA). We also intend to investigate changes to the ctDNA profile by comparing blood samples collected throughout the study.

Study of Olaparib (± Degarelix) Given to Men With Intermediate/High Risk Prostate Cancer Before Prostatectomy

A Study Into the Pharmacodynamic Biomarker Effects of Olaparib (a PARP Inhibitor) ± Degarelix (a GnRH Antagonist) Given Prior to Radical Prostatectomy

Measure the DNA damage response, to compare with effects of or response to two weeks olaparib treatment (± degarelix)

Measure the immunophenotype, e.g. B and T cell subsets, of tumour samples taken at baseline and following 14 days treatment with olaparib (±degarelix) using, for example, IHC and FACS analysis.

Measure biological effects, e.g. reduced tumour proliferation (Ki67), apoptosis (cleaved caspase 3) or altered androgen receptor/ETS regulated gene function in tumour samples taken from patients treated with olaparib.

Measure changes in ctDNA profile following treatment with olaparib (either alone or in combination with degarelix).

Measure the degree of PARP inhibition by comparison of tumour samples taken from men with early prostate cancer at baseline and following treatment with olaparib (either alone or in combination with degarelix). Inhibition of PARP will be measured by the change in IHC levels of biomarkers such as PAR, gamma H2AX, pH2A(s129), Rad51 foci, FancD2 foci and ATM/ATR/CHK1/2.

Determine the incidence and severity of adverse events caused by treatment for 14 days with olaparib (either alone or in combination with degarelix) prior to radical prostatectomy. The severity of adverse events will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.03).

Assess the number of patients who undergo radical prostatectomy on schedule after 14 days of treatment with olaparib (either alone or in combination with degarelix).

To assess preliminary evidence of tumour response, e.g. pathological changes and Prostrate Specific Antigen (PSA) levels, following 14 days treatment with olaparib (±degarelix).

AstraZeneca

Cambridge University Hospitals NHS Foundation Trust

Cambridge Clinical Trials Unit - Cancer Theme

Immune System Diseases

Rare Diseases

Hypersensitivity

Kennedy Disease

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Micronutrients

Vitamins

Androgens

Niraparib

Docetaxel

Abiraterone Acetate

Prednisolone

Pluvicto

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Mineralocorticoids

Ascorbic Acid

Methyltestosterone

Testosterone

Testosterone undecanoate

Testosterone enanthate

Testosterone 17 beta-cypionate

Estrogens, Conjugated (USP)

Estrogens

Tubulin Modulators

Antimitotic Agents

Glucocorticoids

Hormone Antagonists

Antineoplastic Agents, Hormonal

Protective Agents

Cytochrome P-450 Enzyme Inhibitors

Antioxidants

Trace Elements

Anabolic Androgenic Steroids

Anabolic Agents

Radiopharmaceuticals

Vitamin C

SoC (ADT + ARSI ± docetaxel + local RT) + SABR

SoC (ADT + ARSI ± docetaxel ± local RT)

SoC (ADT + ARSI ± docetaxel ± local RT) + 177Lu-PSMA-617

SoC (ADT + Apalutamide ± docetaxel ± local RT)

SoC (ADT ± docetaxel ± local RT) + Nira-AA+P

SABR is a way of giving focused high-dose radiotherapy. SABR given with a dose fractionation schedule of 30Gy in 3-5 fractions over 1-2 weeks to up to 5 metastatic lesions in the bone and/or non-regional (extra-pelvic) lymph nodes.

Stereotactic Ablative Body Radiotherapy (SABR)

177Lu-PSMA-617 is a nuclear medicine therapy. Patients will receive 177Lu-PSMA-617 to a dose of 7.4GBq. Each cycle will consist of 2 doses, 1 week apart (on day 1 and day 8) and will last 6 weeks. Treatment will be given for up to 3 cycles (6 doses).

177Lu-PSMA-617

Combination product containing Niraparib (PARP inhibitor) and Abiraterone Acetate (ARSI). The regular-strength dual-action tablet (DAT) contains 100 mg niraparib/500mg AA per tablet. Patients take 2 tablets a day and receive a of total dose 200 mg niraparib/1000 mg AA. A low-strength DAT tablet containing 50 mg niraparib/500 mg AA may be available for participants requiring a dose reduction of niraparib.

Niraparib and Abiraterone Acetate Dual Action Tablet DAT

Abiraterone Acetate is an ARSI. Single agent Abiraterone Acetate may be used in patients randomised to receive Niraparib and Abiraterone Acetate.

Apalutamide is an ARSI administered as a 240mg oral dose (four tablets taken together at the same time every day) with or without food. It is given daily in 28-day cycles.

Apalutamide

Long-term, continuous treatment with ADT (bilateral orchidectomy, LHRH agonists or LHRH antagonists) if not previously surgically castrated. The choice of ADT is at the discretion of the investigator. This will be given as standard of care as per local guidelines.

Androgen Deprivation Therapy (ADT)

Second generation ARSI (Abiraterone Acetate and Prednisolone \[AA+P\], Enzalutamide, Apalutamide or Darolutamide). This will be given as standard of care as per local guidelines.

Abiraterone acetate will be administered as a single 1000mg once daily dose (4 tablets to be taken together once a day) with prednisolone 5mg once daily to prevent secondary mineralocorticoid excess.

Enzalutamide will be administered as a 160mg oral dose (four capsules taken together at the same time every day) with or without food. Enzalutamide is administered daily in 28-day cycles.

Apalutamide will be administered as 240mg oral dose (four tablets taken together at the same time every day) with or without food. Apalutamide is administered daily in 28-day cycles. Patients require thyroid function monitoring.

Darolutamide will be administered as 600mg oral dose (two 300mg tablets taken together) with or without food. Darolutamide is administered twice daily in 28-day cycles.

Androgen Receptor Signalling Inhibitor (ARSI)

Either 36.25Gy given in 5 fractions over 1-2 weeks to prostate or 60Gy in 20 fractions over 4 weeks to prostate (± 47Gy in 20 fractions to pelvic lymph nodes ± 51Gy in 20 fractions boost to involved nodes).

Local Radiotherapy

Prednisolone should also be administered 5mg daily using local pharmacy prescribing.

Maximum of 6 cycles every 3 weeks may be given at a dose of 75mg/m2 by IV infusion.

Pamela Niem

Lorna O'Shea

Louise Brown

Nick James

STAMPEDE2 is a clinical trial comparing three new treatments with standard of care in people with prostate cancer that has spread to other parts of the body and is responsive to hormone therapy. People from all backgrounds and ethnicities are encouraged to take part and multiple hospitals across the UK are involved. University College London is running the trial.

Each comparison within the trial has its own control arm where people get the best standard of care (Arm A) versus a research arm where a new treatment is added to standard of care.

Participants are allocated to an arm by a computerised system with a 50% chance of getting the research treatment.

Comparison S: Arm A versus Arm S (Stereotactic Ablative Body Radiotherapy (SABR)) - Tests whether giving targeted doses of radiotherapy (SABR) to parts of the body where the cancer has spread slows the spread of the cancer and improves survival. 2476 people will be in this comparison.

Comparison P: Arm A versus Arm P (PSMA-Lutetium (177Lu-PSMA-617)) - Tests whether giving a radioactive material (177Lu-PSMA-617) that targets prostate cancer cells slows the spread of the cancer and improves survival. 1756 people will be in this comparison.

Comparison N: Arm A(N) versus Arm N (Niraparib-Abiraterone Acetate+Prednisolone (Nira-AA+P)) - Tests whether giving a new drug (Nira-AA+P) slows the spread of the cancer and improves survival. Only people with certain genetic changes in their tumour sample can take part in Comparison N. 682 people will be in this comparison.

Participants may be able to take part in more than one comparison.

All participants will be followed up with scans and tests to monitor their cancer. Doctors will check for any side effects from the treatments. Treatments will be stopped if side effects are serious, or people no longer wish to take the treatments.

Platform trial testing three research comparisons where patients are randomised either to experimental treatments in Arms S, P and N or their corresponding SoC control Arms A and A(N).

A Randomised Controlled Platform Trial Testing Treatments in Metastatic Hormone Sensitive Prostate Cancer

Studying Treatments in Patients Receiving Androgen Deprivation Therapy (ADT) and Androgen Receptor Signalling Inhibitors (ARSI) for Metastatic Prostate Cancer: Evaluation of Drug and Radiation Efficacy: A 2nd Multi-arm Multi-stage Randomised Controlled Trial (STAMPEDE2).

Data will be shared according to the CTU's controlled access approach based on principles outlined in the trial protocol.

Requests for sharing data will need to provide detail on the specific requirements, proposed research, qualifications of researchers and publication plan. All non-identifiable data will be available for sharing if approved following the CTU review process. Access to the digital image repository and the stored pathological tissue from researchers outside of the MRC CTU will be obtained through a formal data sharing application detailing the specific requirements, proposed research, investigator qualifications and publication plan. Applications for access to tissue are required separately from access to the shared clinical data.

rPFS is defined as the time from randomisation to progression of metastatic prostate cancer confirmed by radiographic imaging or death from any cause. The definition for rPFS requires at least one of the following four criteria to be met:

1. Radiological metastatic progression by RECIST v1.1,
2. Progression of bone metastases as defined by PCWG3,
3. Symptomatic skeletal-related events secondary to cancer progression,
4. Death from any cause.

Note: Dual-primary outcomes of radiographic Progression-Free-Survival (rPFS) and Overall Survival (OS).

The final reporting times of rPFS for each comparison below will depend on the recruitment rates and the accuracy of assumed median survival times in the sample size calculations.

OS is defined as time from randomisation to death from any cause.

Note: Dual-primary outcomes of radiographic Progression-Free-Survival (rPFS) and Overall Survival (OS).

The final reporting times of OS for each comparison below will depend on the recruitment rates and the accuracy of assumed median survival times in the sample size calculations. Please note that a closed test approach has been used for OS as a dual primary outcome. Continuation of FU for OS will be dependent on observing a significant result for rPFS.

Time from randomisation until the first of:

* Biochemical progression
* Local progression
* Pelvic Lymph node progression
* Distant metastases development or progression
* Skeletal Related Event (where confirmed disease progression)
* Death from prostate cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Olaparib (± Degarelix) Given to Men With Intermediate/High Risk Prostate Cancer Before Prostatectomy	NCT02324998	Prostate Cancer	Olaparib Degarelix	18 Years - 73 Years	Cambridge University Hospitals NHS Foundation Trust
A Randomised Controlled Platform Trial Testing Treatments in Metastatic Hormone Sensitive Prostate Cancer	NCT06320067	Prostate Cancer...	Stereotactic Ab... 177Lu-PSMA-617 Niraparib and A... Abiraterone Ace... Apalutamide Androgen Depriv... Androgen Recept... Local Radiother... Prednisolone Docetaxel	18 Years -	University College, London
A Randomised Controlled Platform Trial Testing Treatments in Metastatic Hormone Sensitive Prostate Cancer	NCT06320067	Prostate Cancer...	Stereotactic Ab... 177Lu-PSMA-617 Niraparib and A... Abiraterone Ace... Apalutamide Androgen Depriv... Androgen Recept... Local Radiother... Prednisolone Docetaxel	18 Years -	University College, London
Study of Olaparib (± Degarelix) Given to Men With Intermediate/High Risk Prostate Cancer Before Prostatectomy	NCT02324998	Prostate Cancer	Olaparib Degarelix	18 Years - 73 Years	Cambridge University Hospitals NHS Foundation Trust

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