Additional Treatments to the Local Tumour for Metastatic Prostate Cancer: Assessment of Novel Treatment Algorithms

TITLE: Additional Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel Treatment Algorithms (ATLANTA)

OBJECTIVES: To determine whether the addition of local treatment to the prostate (minimally invasive therapy or radical therapy \[prostatectomy or radiotherapy\]), including selective metastases-directed therapy, improves oncological outcomes in men receiving standard of care treatment for newly diagnosed metastatic prostate cancer

PHASE: Phase II Randomised Control Trial (RCT) incorporating an internal pilot

DESIGN: Three-arm unblinded randomised controlled trial using a positive control

SAMPLE SIZE: 432

POPULATION: Men who are willing to undergo local therapy to the prostate and selective metastases-directed therapy for metastatic prostate cancer in addition to standard care systemic treatment.

STUDY HYPOTHESIS: We hypothesise that men with metastatic disease who undergo treatment of the local tumour in the form of either radical therapy (prostatectomy or radiotherapy) or minimally invasive ablative therapy (MIAT), combined with metastases directly therapy, will have improved survival compared to those who receive standard of treatment alone. We will be investigating this newly evolving treatment paradigm in a formal randomised control trial (RCT).

TREATMENT/MAIN STUDY PROCEDURES: (including treatment duration and follow-up) Our pragmatic design ensures all eligible patients can be approached and randomised as there is no requirement for fitness to undergo RP. The design also incorporates the latest approach for standard of care as well as management of lymph nodes.

Arm 1*: Standard of Care (SOC) treatment as determined by treating physician (positive control) (androgen deprivation with or without Docetaxel chemotherapy or other systemic/local directed standard of care treatment including but not limited to Abiraterone or Enzalutamide). Radiotherapy in this arm defined as palliative/cytoreductive in high volume metastases or to mirror STAMPEDE local radiotherapy arm in low volume metastases.

Arm 2**: Minimally Invasive Ablative Therapy (MIAT) to local tumour / prostate in addition to SOC systemic treatment. Predominantly cryotherapy but based on disease characteristics, HIFU also. Metastases directed therapy declared prior to randomisation.

Arm 3**: Radical therapy (Prostatectomy or External beam radiotherapy \[60Gy x 20 or 74Gy + in 32-37 weeks\]) in addition to SOC systemic treatment. Modality based on physician and patient preference and patient co-morbidities. Metastases directed therapy declared prior to randomisation.

FOLLOW-UP DURATION: Until progression or minimum 2-years or maximum 4 years whichever is first (or 6 months for the Pilot if the trial does not progress to Phase II).

Prior to enrolment all patients must undergo Standard of Care (SOC) staging investigations for localised and metastatic disease and will need to have histologically proven local disease within the prostate. There will be no restriction on the type of biopsy used for diagnosis.

*ADT but not chemotherapy may be initiated prior to recruitment.The decision as to which SOC systemic therapy regimen will be used is by the treating clinician and/or clinical team (to be declared upfront prior to randomisation). If radiotherapy is planned for local disease in some cases in the SOC arm then this will be declared upfront prior to randomisation by the treating physician. Similarly, if lymph node radiotherapy is to be advocated then this is to be declared upfront prior to randomisation by the treating physician and can be applied to any one of the three arms. Randomisation into a treatment arm would occur at the time of recruitment which would be within 3 months of starting SOC systemic therapy.

Extra blood and urine samples will be identified using a special study number assigned to each patient, in such a way that the scientists analysing them will not be able to find out patients identity.

• Standard of Care (Combination product): Androgen deprivation with or without docetaxel chemotherapy, Abiraterone, Enzalutamide or any other proven agent) treatment as determined by treating physician (positive control).
• Minimally Invasive Ablative Therapy (MIAT) (Procedure), also known as Metastatic Directed Therapy (MDT): MIAT includes High intensity focused ultrasound (HIFU) or Cryotherapy to the prostate. Metastatic Directed Therapy available for use.
• Radical Therapy (Prostatectomy or Radiotherapy) (Procedure), also known as Metastatic Directed Therapy (MDT): Radical therapy includes: Prostatectomy (any surgical approach) or External beam radiotherapy (High dose). Metastatic Directed Therapy available for use.

Primary outcomes

• Prostate cancer on post-standard of care prostate biopsy. [6 months]: Proportion of patients with complete pathological response, measured on post SOC (systemic therapy) prostate biopsies (Internal Pilot).
• Safety (Adverse Events) [2-4 years (continuous)]: Safety (Adverse Events), measured using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, Grade 1-5.
• Progression-free survival (PFS) [2-4 years]: Progression-free survival (PFS), measured as a composite outcome of Biochemical failure (PSA progression value) or Local progression or Lymph node progression or Bone metastases progression (new sites) or Progression or development of new distant metastases, defined as lymph nodes outside the pelvis, bone or organ involvement or Skeletal-related events confirmed as progression as in the Systemic Therapy in Advancing Or Metastatic Prostate Cancer: Evaluation Of Drug Efficacy (STAMPEDE) RCT).

Secondary outcomes

• Urinary side effects [Baseline, week 26, 52, then at 24 months.]: Urinary side effects, measured using the IPSS questionnaire, Score 0-35.
• Sexual side effects [Baseline, week 26, 52, then at 24 months.]: Sexual side effects, measured using the IIEF15 questionnaire, Score 0-75.
• Rectal side effects [Baseline, week 26, 52, then at 24 months.]: Rectal side effects, measured using the EPIC bowel and bladder questionnaire, Score 14-113.
• Progression (Biochemical / Radiological / Clinical) [Baseline, week 12, 26, 34, 52 then every every 24 weeks for remaining years 2 to 4 and Imaging tests at baseline and if progression is suspected by a clinician]: Progression on PSA and imaging and impact of clinical features on progression, measured using PSA blood tests
• Health-related quality-of-life [Baseline, week 26, 52, then at 24 months.]: Health-related quality-of-life, measured using EuroQol (EQ-5D-5L) questionnaire, Score 0-100.

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

1. Diagnosed with prostate cancer within 6 months of screening visit
2. Metastatic disease (Any T, Any N, M1+) of any grade, stage or Prostate Specific Antigen (PSA) level.
3. Fit to undergo standard of care treatment for metastatic disease and both minimally invasive therapy and prostate radiotherapy/prostatectomy.
4. Performance status 0-2
5. Histologically proven local tumour

Exclusion Criteria:

1. Patient did not undergo and/or is unable to undergo standard of care baseline imaging tests for confirmation of metastatic status (CT abdomen/pelvis AND chest Xray (or CT chest) AND radioisotope bone scan (or whole body imaging such as MRI or PET imaging as alternative to all preceding scans mentioned here) AND prostate MRI.
2. Prior exposure to long-term androgen deprivation therapy or hormonal therapy for the treatment of prostate cancer unless started within 6 months of screening visit.
3. Prior chemotherapy or local or systemic therapy for treatment of prostate cancer (apart from ADT or hormonal therapy as outlined above)

• Results publication: Connor MJ, Shah TT, Smigielska K, Day E, Sukumar J, Fiorentino F, Sarwar N, Gonzalez M, Falconer A, Klimowska-Nassar N, Evans M, Naismith OF, Thippu Jayaprakash K, Price D, Gayadeen S, Basak D, Horan G, McGrath J, Sheehan D, Kumar M, Ibrahim A, Brock C, Pearson RA, Anyamene N, Heath C, Shergill I, Rai B, Hellawell G, McCracken S, Khoubehi B, Mangar S, Khoo V, Dudderidge T, Staffurth JN, Winkler M, Ahmed HU. Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial. BMJ Open. 2021 Feb 25;11(2):e042953. doi: 10.1136/bmjopen-2020-042953. PMID 33632752

• Hashim U Ahmed, FRCS Urol, Principal investigator, Imperial College London