Sequencing Abiraterone and Enzalutamide in mCRPC
|ClinicalTrials.gov Identifier: NCT02125357|
Recruitment Status : Active, not recruiting
First Posted : April 29, 2014
Last Update Posted : February 2, 2017
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.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Castration-Resistant Prostate Cancer||Drug: Abiraterone acetate Drug: Enzalutamide||Phase 2|
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 (Clinical Trial)|
|Actual Enrollment :||202 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Randomized Phase II Study of Sequencing Abiraterone Acetate and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer|
|Actual Study Start Date :||September 2014|
|Estimated Primary Completion Date :||July 2018|
|Estimated Study Completion Date :||July 2018|
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 Name: Zytiga
B - Enzalutamide
160mg PO OD as per standard of care, or until PSA progression then cross-over to Arm A.
160mg PO OD as per standard of care.
Other Name: Xtandi
- 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 ]
- Potential biomarkers that are associated with treatment efficacy and/ or resistance [ Time Frame: 1 year ]Among mCRPC patients receiving abiraterone acetate and enzalutamide
- PSA response rate in mCRPC patients treated with first-line abiraterone acetate or enzalutamide [ Time Frame: 1 year ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02125357
|Canada, British Columbia|
|BC Cancer Agency - Abbotsford|
|Abbotsford, British Columbia, Canada, V2S 0C2|
|BC Cancer Agency - Southern Interior|
|Kelowna, British Columbia, Canada, V1Y 5L3|
|BC Cancer Agency - Centre for the North|
|Prince George, British Columbia, Canada, V2N 7E9|
|BC Cancer Agency - Fraser Valley|
|Surrey, British Columbia, Canada, V3V 1Z2|
|Vancouver Prostate Centre|
|Vancouver, British Columbia, Canada, V5Z 1M9|
|BC Cancer Agency - Vancouver Centre|
|Vancouver, British Columbia, Canada, V5Z 4E6|
|BC Cancer Agency - Vancouver Island|
|Victoria, British Columbia, Canada, V8R 6V5|
|Study Chair:||Kim N Chi, MD||British Columbia Cancer Agency|