Sequencing Abiraterone and Enzalutamide in mCRPC

August 6, 2020 updated by: British Columbia Cancer Agency

A Randomized Phase II Study of Sequencing Abiraterone Acetate and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer

This study is being offered to patients who have castrate-resistant (also known as hormone-refractory) prostate cancer. The cancer has metastasized or spread outside the prostate area to other parts of the body.

The purpose of this study is to evaluate the effects of sequencing hormonal therapies (abiraterone acetate and enzalutamide) and to assess treatment efficacy of these two agents.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Abiraterone acetate and enzalutamide have emerged as standard therapies in metastatic castration-resistant prostate cancer (mCRPC). Both agents improve outcomes in patients previously treated with docetaxel and in those that are chemotherapy-naive. Although their mechanisms of action differ, both abiraterone and enzalutamide target persistent androgen receptor (AR) signaling. Abiraterone inhibits CYP17 and testicular and extragonadal androgen production whereas enzalutamide directly antagonises the AR. Whether cross resistance occurs between these agents if used in sequence is unknown, but theoretically disparate mechanisms of resistance may allow for successful sequencing of these agents. Prior studies have reported Prostate-Specific Antigen (PSA) response rates of under 10% in patients treated with abiraterone after enzalutamide and 13%-29% in patients treated with enzalutamide after abiraterone. Since these data were generated in small, retrospective series, a prospective clinical trial is warranted to evaluate effects of sequencing abiraterone and enzalutamide. A randomised phase II study is proposed in which patients with PSA progression on abiraterone or enzalutamide will be crossed over to the opposite agent. Although not a surrogate for clinical outcomes, PSA changes will be used to assess treatment efficacy since PSA expression is driven by AR activation.

Apart from determining optimal sequencing of abiraterone and enzalutamide in mCRPC patients, a key issue associated with the use of these agents is identifying circulating biomarkers associated with treatment response and resistance. Our group has preliminary data showing that a high proportion of enzalutamide-resistant mCRPC patients and some abiraterone-resistant mCRPC patients possess focal AR amplification in cell-free tumour DNA extracted from plasma. In pre-clinical studies, other potential mechanisms of resistance to these agents include increased expression of AR splice variants (abiraterone and enzalutamide) increased expression of CYP17 (abiraterone), upregulation of the stress-activated chaperone protein clusterin (enzalutamide only) and a point mutation (F876L) in the ligand-binding domain of the AR (enzalutamide only). Non-coding RNAs (ncRNAs) are additional biomarkers of interest since they are implicated in tumorigenesis and are readily detectable in plasma of mCRPC patients. Examination of these biomarkers in serum and plasma is planned, with the aim of identifying potentially novel factors associated with treatment efficacy and resistance in mCRPC patients receiving abiraterone and enzalutamide.

The cognitive effects of abiraterone and enzalutamide are not well described. Enzalutamide is known to cross the blood-brain barrier and infrequently causes seizures, possibly related to effects on the γ-aminobutyric acid-gated chloride channel. In the enzalutamide registration study, a small subset (< 5%) of patients also developed mental impairment disorders including amnesia, memory impairment, cognitive disorder and disturbance in attention. Conversely, no central nervous system effects of abiraterone have been reported. Cognitive testing will therefore be undertaken in this study to evaluate potential differences between these agents.

Study Type

Interventional

Enrollment (Actual)

202

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Abbotsford, British Columbia, Canada, V2S 0C2
        • BC Cancer Agency - Abbotsford
      • Kelowna, British Columbia, Canada, V1Y 5L3
        • BC Cancer Agency - Southern Interior
      • Prince George, British Columbia, Canada, V2N 7E9
        • BC Cancer Agency - Centre for the North
      • Surrey, British Columbia, Canada, V3V 1Z2
        • BC Cancer Agency - Fraser Valley
      • Vancouver, British Columbia, Canada, V5Z 1M9
        • Vancouver Prostate Centre
      • Vancouver, British Columbia, Canada, V5Z 4E6
        • BC Cancer Agency - Vancouver Centre
      • Victoria, British Columbia, Canada, V8R 6V5
        • BC Cancer Agency - Vancouver Island

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  1. Willing and able to provide informed consent
  2. Adult males ≥ 18 years age
  3. History of adenocarcinoma of the prostate diagnosed histologically without evidence of neuroendocrine or small cell differentiation
  4. Prior surgical orchiectomy or if on luteinizing hormone-releasing hormone (LHRH) agonist/antagonist then testosterone < 1.7 nmol/L at screening visit (patients must maintain LHRH agonist/antagonist therapy for duration of study treatment if not surgically castrated)
  5. Evidence of metastatic disease on bone scan or CT scan

  6. Evidence of biochemical or imaging progression in the setting of surgical or medical castration. Progressive disease for study entry is defined by one of the following three criteria:

    1. PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement. Minimum PSA at screening visit is > 2.0 ug/L
    2. Soft tissue or visceral disease progression (see Appendix B for definition of measurable disease as per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria)
    3. Bone progression: ≥ 2 new lesions on bone scan
  7. ECOG performance status 0-2 (see Appendix C)
  8. Eligible for treatment with either abiraterone acetate or enzalutamide as per standard of care guidelines

  9. Adequate organ function defined as:

    1. Absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L and hemoglobin ≥ 80 g/L
    2. Creatinine clearance ≥ 30 ml/min (calculated by Cockcroft-Gault formula, see Appendix D)
    3. Serum potassium within normal limits
    4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome (direct bilirubin ≤ 1.5 x ULN)
    5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN
  10. Able to swallow study drug and comply with study requirements including provision of peripheral blood samples at specified time points for correlative studies
  11. Recovery from all prior treatment-related toxicity to grade ≤ 2 (as per Common Terminology Criteria for Adverse Events 4.0)

Exclusion Criteria:

  1. Severe concurrent illness or co-morbid disease that would make the subject unsuitable for enrolment
  2. Prior therapy with CYP17 inhibitors (including abiraterone acetate, TAK-700, TOK-001 and ketoconazole), enzalutamide or other experimental anti-androgens (e.g. ARN-509, TOK-001)
  3. Prior systemic chemotherapy for mCRPC
  4. Life expectancy < 6 months
  5. Active concurrent malignancy (with the exception of non-melanomatous skin cancer)
  6. Wide-field radiotherapy or radioisotopes such as Strontium-89 or Radium-223 ≤ 28 days prior to starting study drug (limited-field palliative radiotherapy for 1-5 fractions is permitted at anytime prior to commencement protocol therapy)
  7. Brain metastases or active epidural disease (treated epidural disease is permitted)
  8. Use of herbal products that may lower PSA level (e.g. saw palmetto)
  9. Contraindication to prednisone therapy including poorly controlled diabetes mellitus
  10. History of seizure or seizure disorder, or history of any cerebrovascular event within 6 months of study entry.
  11. Gastrointestinal disorder affecting absorption
  12. Major surgery within 4 weeks of starting study treatment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: A - Abiraterone Acetate
Abiraterone acetate 1000mg PO OD with prednisone 5mg PO BID or 10mg OD as per standard of care, or until PSA progression then cross-over to Arm B.
Drug: Abiraterone acetate
Abiraterone acetate 1000mg PO OD with prednisone 5mg PO BID or 10mg OD as per standard of care.
Other Names:
  • Zytiga
Other: B - Enzalutamide
160mg PO OD as per standard of care, or until PSA progression then cross-over to Arm A.
Drug: Enzalutamide
160mg PO OD as per standard of care.
Other Names:
  • Xtandi

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
PSA response rate in mCRPC patients with PSA progression on first-line therapy when crossed over to second-line therapy with the opposite agent
Time Frame: 1 year
1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Potential biomarkers that are associated with treatment efficacy and/ or resistance
Time Frame: 1 year
Among mCRPC patients receiving abiraterone acetate and enzalutamide
1 year

Other Outcome Measures

Outcome Measure
Time Frame
PSA response rate in mCRPC patients treated with first-line abiraterone acetate or enzalutamide
Time Frame: 1 year
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

British Columbia Cancer Agency

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2014

Primary Completion (Actual)

February 4, 2020

Study Completion (Actual)

February 4, 2020

Study Registration Dates

First Submitted

April 22, 2014

First Submitted That Met QC Criteria

April 27, 2014

First Posted (Estimate)

April 29, 2014

Study Record Updates

Last Update Posted (Actual)

August 7, 2020

Last Update Submitted That Met QC Criteria

August 6, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GUTG-001

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Metastatic Castration-Resistant Prostate Cancer

Clinical Trials on Abiraterone acetate

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Bahrain

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe