Prostate Advances in Comparative Evidence (PACE)

• ClinicalTrials.gov Identifier: NCT01584258
• Recruitment Status: Active, not recruiting
• First Posted: April 24, 2012
• Last Update Posted: January 19, 2024
• Sponsor: Royal Marsden NHS Foundation Trust
• Collaborator: The Institute of Cancer Research, Sutton, Surrey, UK
• Information provided by (Responsible Party): Royal Marsden NHS Foundation Trust

Tracking Information

• First Submitted Date: April 22, 2012
• First Posted Date: April 24, 2012
• Last Update Posted Date: January 19, 2024
• Actual Study Start Date: August 7, 2012
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 18, 2024)

• PACE-B and PACE-C: Freedom from biochemical or clinical failure [ Time Frame: 5 years from randomisation (primary timepoint) ]
  Biochemical progression is defined as: Phoenix definition Clinical progression is defined as: commencement (PACE-B) or re-commencement (PACE-C) of androgen deprivation therapy, local recurrence, nodal recurrence and distant metastases
• PACE-A: Co-primary patient reported outcomes of urinary incontinence and bowel bother [ Time Frame: 2 years from treatment (primary timepoint) ]
  Urinary incontinence assessed by the number of absorbent pads required per day to control leakage measured by The Expanded Prostate Cancer Index (EPIC) questionnaire. Bowel bother assessed by summary score from the EPIC questionnaire.

Original Primary Outcome Measures (submitted: April 22, 2012)

Biochemical disease-free survival [ Time Frame: 5 years (primary timepoint) ]

Biochemical progression is defined as follows: For conventional radiation and radiosurgery arms: Serum PSA of at least 2 ng/mL greater than the post-radiotherapy nadir (lowest PSA to date)(Phoenix definition); for surgical arm: PSA > 0.2 ng/mL. For either arm, a recommencement of androgen deprivation also counts as biochemical failure.

Current Secondary Outcome Measures (submitted: January 18, 2024)

• All arms: Clinician reported acute toxicity [ Time Frame: 10 years ]
  CTCAE and RTOG (SBRT and conventional RT patients) or Clavien scale (surgical patients).
• All arms: Clinician reported late toxicity [ Time Frame: 10 years ]
  CTCAE and RTOG (SBRT and conventional RT patients only).
• All arms: Patient reported acute and late bowel, bladder and erectile dysfunction symptoms. [ Time Frame: 10 years ]
  Assessed using International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS), Vaizey score, and Expanded Prostate Index Composite-26 (EPIC-26) instruments.
• All arms: Disease-specific and overall survival [ Time Frame: 10 years ]
  Disease-specific and overall survival
• All arms: Progression-free survival [ Time Frame: 10 years ]
  Radiographic, clinical or biochemical evidence of local or distant failure
• PACE-A and PACE-B: Commencement of androgen deprivation therapy; PACE-C: Re-commencement of androgen deprivation therapy [ Time Frame: 10 years ]
  LHRH analogues, anti-androgens, orchidectomy
• PACE-A: Freedom from biochemical or clinical failure [ Time Frame: 5 years from randomisation (primary timepoint) ]
  Biochemical progression is defined as: Phoenix definition (SBRT arm) or >0.2ng/ml (surgical arm) Clinical progression is defined as: commencement of androgen deprivation therapy, local recurrence, nodal recurrence and distant metastases

Original Secondary Outcome Measures (submitted: April 22, 2012)

• Cause-specific and overall survival [ Time Frame: 10 years ]
  Cause-specific survival will include deaths from prostate cancer only. Overall survival will include deaths from any cause.
• Progression-free survival [ Time Frame: 10 years ]
  Radiographic or clinical evidence of local, regional or distant failure.
• Toxicities associated with surgery, radiotherapy and radiosurgery [ Time Frame: 10 years ]
  Assessed by CTCAE version 4
• Quality of Life [ Time Frame: 10 years ]
  Using EORTC Quality of Life Questionnaire PR-25

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Prostate Advances in Comparative Evidence
• Official Title: International Randomised Study of Prostatectomy vs Stereotactic Body Radiotherapy (SBRT) and Conventionally Fractionated Radiotherapy vs SBRT for Organ-Confined Prostate Cancer
• Brief Summary: This study is an international multicentre randomised study of low, intermediate, and high risk prostate cancer and is composed of three parallel randomisation schemes based on applicability of surgery as a treatment for the patient and risk group. Low and intermediate risk patients, for whom surgery is a consideration, are randomised to either prostatectomy or prostate SBRT. Low and intermediate risk patients, for whom surgery is not a consideration, are randomised to either conventionally fractionated radiotherapy or prostate SBRT. Intermediate and high risk patients, for whom ADT treatment is indiacted and surgery is not a consideration, are randomised to either conventionally fractionated radiotherapy or prostate SBRT. Efficacy, toxicity and quality of life outcomes will be compared across the pairs in each randomisation.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Multicentre, international phase 3 randomised controlled study comprising three parallel randomisations with a common experimental arm.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Prostate Cancer

Intervention

• Procedure: Prostatectomy
  Radical prostatectomy: performed open, laparoscopically or using a robotically assisted laparoscopic approach.
• Radiation: Conventionally Fractionated Prostate Radiotherapy

  Conventional fractionation delivered to a dose of:

  (PACE-B) 78 Gy in 39 fractions or 62 Gy in 20 fractions; (PACE-C) 60 Gy in 20 fractions

• Radiation: Prostate SBRT
  Prostate SBRT delivered to a dose of 36.25 Gy in 5 fractions.

Study Arms

• Active Comparator: PACE-A: Prostatectomy vs prostate SBRT
  Low and intermediate risk patients, for whom surgery is considered, will be randomised to prostatectomy vs prostate SBRT delivered with 36.25 Gy in 5 fractions.
  Interventions:

  • Procedure: Prostatectomy
  • Radiation: Prostate SBRT
• Active Comparator: PACE-B: Conventionally Fractionated RT vs Prostate SBRT
  Low and intermediate risk patients, for whom surgery is not considered or who refuse surgery, will be randomised to either conventionally fractionated radiotherapy delivered to a dose of 78 Gy in 39 fractions or 62 Gy in 20 fractions vs SBRT delivered with 36.25 Gy in 5 fractions.
  Interventions:

  • Radiation: Conventionally Fractionated Prostate Radiotherapy
  • Radiation: Prostate SBRT
• Active Comparator: PACE-C: Conventionally Fractionated RT vs Prostate SBRT
  Intermediate and high risk patients, indicated for 6 months ADT, will be randomised to either conventionally fractionated radiotherapy delivered to a dose of 60 Gy in 20 fractions vs SBRT delivered with 36.25 Gy in 5 fractions.
  Interventions:

  • Radiation: Conventionally Fractionated Prostate Radiotherapy
  • Radiation: Prostate SBRT

Publications *

• Tree AC, Ostler P, van der Voet H, Chu W, Loblaw A, Ford D, Tolan S, Jain S, Martin A, Staffurth J, Armstrong J, Camilleri P, Kancherla K, Frew J, Chan A, Dayes IS, Duffton A, Brand DH, Henderson D, Morrison K, Brown S, Pugh J, Burnett S, Mahmud M, Hinder V, Naismith O, Hall E, van As N; PACE Trial Investigators. Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2022 Oct;23(10):1308-1320. doi: 10.1016/S1470-2045(22)00517-4. Epub 2022 Sep 13. Erratum In: Lancet Oncol. 2023 May;24(5):e192.
• Brand DH, Tree AC, Ostler P, van der Voet H, Loblaw A, Chu W, Ford D, Tolan S, Jain S, Martin A, Staffurth J, Camilleri P, Kancherla K, Frew J, Chan A, Dayes IS, Henderson D, Brown S, Cruickshank C, Burnett S, Duffton A, Griffin C, Hinder V, Morrison K, Naismith O, Hall E, van As N; PACE Trial Investigators. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. Lancet Oncol. 2019 Nov;20(11):1531-1543. doi: 10.1016/S1470-2045(19)30569-8. Epub 2019 Sep 17.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 18, 2024): 2205
• Original Estimated Enrollment (submitted: April 22, 2012): 1036
• Estimated Study Completion Date: December 2027
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion critieria (all arms):

• Histological confirmation of prostate adenocarcinoma within the last 18 months (unless on active surveillance and not clinically indicated)
• Men aged ≥18 years at randomisation
• WHO performance status 0 - 2
• Patients considered candidates for surgery are eligible for PACE-A; patients not considered candidates for surgery and patients who decline surgery or prefer to avoid surgery are eligible for PACE-B and PACE-C.
• Ability of the research subject to understand and the willingness to sign a written informed consent document.

Specific risk stratification inclusion criteria for PACE-A and PACE-B:

• Minimum of 10 biopsy cores.
• Gleason score ≤ 3+4
• Clinical and/or MRI stage T1c -T2c, N0-X, M0-X
• PSA ≤ 20 ng/ml (completed within 60 days of randomisation)
• Patients belonging to one of the following risk groups:

• Low risk - patients with tumours meeting all of the following criteria:

  • Gleason ≤ 6
  • Clinical stage T1-T2a
  • PSA < 10 ng/ml (within 60 days prior to randomisation)

• Intermediate risk - patients with tumours meeting any one of the following criteria:

  • Gleason 3+4
  • Clinical stage T2b or T2c
  • PSA 10-20 ng/ml (within 60 days prior to randomisation)

Specific risk stratification inclusion criteria for PACE-C:

• Patient planned for a minimum of 6 months ADT (maximum of 12 months). Patients receiving extended androgen deprivation therapy (18 months maximum) to permit safe delay of radiotherapy as a result of the COVID19 pandemic (only) are eligible.
• Gleason score ≤ 4+4
• MRI stage T1c -T3a, N0-X, M0-X
• PSA ≤ 30 ng/ml (within 60 days prior to starting ADT)
• Patients belonging to one of the following risk groups:

• Intermediate risk - includes the presence of any of the following, assuming no high risk features apply:

  • Gleason 7 (3+4 or 4+3)
  • T2 (N0, M0-X)
  • PSA 10-20 ng/ml

• High risk - patients with tumours that meet a maximum of 2 of the following criteria:

  • Gleason 4+4 (max ≤ 50% cores)
  • T3a (N0, M0)
  • PSA >20 ng/ml

Exclusion criteria (all arms):

• Previous malignancy within the last 2 years (except basal cell carcinoma or squamous cell carcinoma of the skin), or if previous malignancy is expected to significantly compromise 5 year survival.
• Prior pelvic radiotherapy.
• Prior androgen deprivation therapy (including androgen agonists and antagonists) for PACE-A and PACE-B participants.
• Any prior active treatment for prostate cancer (with the exception of ADT for PACE-C participants). Patients previously on active surveillance are eligible if they continue to meet all other eligibility criteria.
• Life expectancy <5 years.
• Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artefacts.
• Medical conditions likely to make radiotherapy inadvisable eg inflammatory bowel disease, significant urinary symptoms.
• For patients having fiducials inserted: Anticoagulation with warfarin/ bleeding tendency making fiducial placement or surgery unsafe in the opinion of the clinician.
• Participation in another concurrent treatment protocol for prostate cancer.

Specific exclusion criteria for PACE-C:

• >14 weeks of androgen deprivation therapy prior to randomisation
• Medical conditions likely to make ADT inadvisable (e.g. significant and ongoing cardiac issues).

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Ireland, New Zealand, United Kingdom

Administrative Information

• NCT Number: NCT01584258
• Other Study ID Numbers: CCR3766
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Royal Marsden NHS Foundation Trust
• Original Responsible Party: Accuray Incorporated
• Current Study Sponsor: Royal Marsden NHS Foundation Trust
• Original Study Sponsor: Accuray Incorporated
• Collaborators: The Institute of Cancer Research, Sutton, Surrey, UK

Investigators

• Study Director: Nicholas van As, MD; Royal Marsden NHS Foundation Trust, London, United Kingdom
• Principal Investigator: Peter Ostler, MD; Mount Vernon Cancer Centre, United Kingdom
• Principal Investigator: Alison Tree, MD; Royal Marsden NHS Foundation Trust, London, United Kingdom

• PRS Account: Royal Marsden NHS Foundation Trust
• Verification Date: January 2024