Sequencing Abiraterone and Enzalutamide in mCRPC

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.

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.

Eligibility Criteria:
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