Patients may or may not have been treated previously with a nonsteroidal antiandrogen, such as flutamide, bicalutamide or nilutamide; for patients previously treated with an antiandrogen, they must be off treatment for at least 4 weeks (for flutamide) or 6 weeks (for bicalutamide or nilutamide) prior to registration and must have shown PSA progression after discontinuing the anti-androgen
Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both LHRH agonist and oral anti-androgen) is =< 45 days prior to the date of registration
Patients on long term (> 6 months) anti-androgen therapy (e.g., flutamide, bicalutamide, nilutamide) will need to be off anti-androgen for 4 weeks (wash out period) and show evidence of disease progression off the anti-androgen; patients that have been on an anti-androgen 6 months or less will need to discontinue anti-androgen therapy prior to treatment start (no wash out period required)
Preceding line of treatment included response to anti-androgen, progression documented after withdrawal of the anti-androgen.
Receipt of >1 line of therapy that includes a second generation androgen inhibitor for treatment of mCRPC
Prior exposure to enzalutamide, ARN-509, or other investigational androgen receptor (AR)-directed therapy
Patients may not have received enzalutamide or ARN-509 (another androgen receptor antagonist) in the past
Patients treated with first generation anti-androgen as most recent systemic therapy (bicalutamide, nilutamide) must have at least 4 weeks elapsed from treatment discontinuation to start of protocol therapy with evidence of disease progression by Prostate Cancer Working Group 2 (PCWG2) criteria following discontinuation of prior anti-androgen
Previous androgen suppression therapy is allowed if it was completed at least 3 months prior to initiation of study treatment
Subjects on long term (>= 6 months) first generation anti-androgen therapy (e.g. flutamide, bicalutamide, nilutamide) will need to discontinue anti-androgen therapy for 4 weeks prior to registration (wash out period) and show evidence of disease progression off the anti-androgen; subjects that have been on a first generation anti-androgen 6 months or less will need to discontinue therapy prior to registration (no wash out period required)
Subjects on second generation anti-androgen therapy (enzalutamide) or androgen bio-synthesis inhibitor (abiraterone acetate) will need to discontinue therapy 2 weeks prior to registration (wash out period)
More than one prior line of therapy with a second generation anti-androgen (enzalutamide, ARN-509, etc.) or androgen bio-synthesis inhibitor (abiraterone acetate, etc.); subject may have had one second generation anti-androgen or androgen bio-synthesis inhibitor but not both sequentially; subjects that have received combination therapy with second generation anti-androgen plus an androgen bio-synthesis inhibitor would be eligible (e.g., enzalutamide plus abiraterone acetate as one line of therapy on a clinical trial)
Subjects must not have received any previous androgen deprivation therapy (LHRH agonist or LHRH antagonist) or cytotoxic therapy for prostate cancer in the metastatic setting\r\n* Exceptions\r\n** Patients may have received no more than 30 days of anti-androgen (e.g. bicalutamide) in the metastatic setting prior to the start of study treatment.
Prior androgen deprivation therapy and/or first generation anti-androgen (e.g. bicalutamide, nilutamide, flutamide) for biochemically recurrent prostate cancer. Prior ADT and/or first generation anti-androgen in the (neo)adjuvant and/or salvage setting before, during, and/or following radiation or surgery is allowed provided last effective dose of ADT and/or first-generation anti-androgen is > 9 months prior to date of randomization and total duration of prior therapy is ? 36 months.
No prior treatment with enzalutamide, ARN-509, ODM-201, galeterone or other investigational androgen receptor (AR) targeted treatment is allowed
Prior treatment with enzalutamide or other potent androgen-receptor blockers, approved or experimental (e.g., ARN-509, ODM-201, or galeterone)
A minimum of 4 weeks elapsed off of anti-androgen therapy prior to enrollment for flutamide and 6 weeks for bicalutamide and nilutamide without evidence of an anti-androgen withdrawal response; patients who NEVER HAD A PSA decline with the most recent anti-androgen therapy or in whom the response to the most recent anti-androgen was for < 3 months require only a 2 week washout period prior to first dose of study drug
Previous treatment with an agent that blocks adrenal androgen synthesis (e.g. abiraterone acetate, TAK-700, TOK-001, ketoconazole) or second generation androgen receptor (AR) antagonists (e.g., BMS 641988, ARN-509,TOK-001)
Prior anti-androgen therapy
Previous androgen suppression therapy for prostate cancer.
Prior androgen suppression therapy for prostate cancer for more than 6 months
Expansion Phase: Patients must have progressed while receiving an androgen-directed therapy, as follows:
Received prior 2nd generation anti-androgen and require urgent disease response or stabilization
Previously treated with enzalutamide or experimental therapies directed against androgen receptor (ie, apalutamide).
At least 1 line of androgen receptor (AR)-targeted therapy (for example {e.g
Candidates for ADT and docetaxel. Started ADT with or without first generation anti androgen, but no longer than 12 weeks before randomization
Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide), 5-alpha reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or biologic therapy within 4 weeks of enrollment (day 1 visit)
Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g. abiraterone, orteronel) in the past 6 months; 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as long as subject has been stable on medication for past 6 months
Subjects who received combined androgen blockade as their first-line hormonal therapy with an antiandrogen must have shown PSA progression after discontinuing the antiandrogen for >= 6 weeks prior to study treatment; no washout is needed after abiraterone or enzalutamide are discontinued; first generation antiandrogens such as bicalutamide must be withdrawn if given as first-line therapy
Hormonal therapy (e.g., androgen receptor [AR] antagonists, 5 alpha reductase inhibitors, estrogens)
Prior exposure to enzalutamide, androgen receptor antagonist ARN-509 (ARN-509) or other investigational AR-directed therapy in the setting of mCRPC
A minimum of 2 weeks elapsed off of antiandrogen therapy prior to registration (i.e. flutamide, nilutamide, and bicalutamide) without evidence of an anti-androgen withdrawal response; an anti-androgen withdrawal response is a PSA level at 2 weeks (or more) off of anti-androgen equal or higher than PSA level when anti-androgen therapy stopped
At least 1 line of prior androgen receptor (AR) targeted therapy
During the Phase II trial, patient must have been treated with enzalutamide or other second-generation androgen receptor antagonist before enrollment into this trial, and is tested positive for AR-V7
Known androgen receptor (AR) positive breast cancer (AR staining > 10% by immunohistochemistry is considered positive); if the AR status is unknown, the patient can go on study
Castrate-resistant disease, defined as follows:\r\n* All patients must have received (and be receiving) standard of care androgen deprivation treatment (surgical castration versus gonadotropin-releasing hormone [GnRH] analogue or antagonist treatment); subjects receiving GnRH analogue or antagonist must continue this treatment throughout the time on this study\r\n* Patients may or may not have been treated previously with a nonsteroidal antiandrogen; for patients previously treated with an antiandrogen, they must be off use of anti-androgen for at least 4 weeks (for flutamide) or 6 weeks (for bicalutamide or nilutamide) prior to registration; moreover, subjects who demonstrate an anti-androgen withdrawal response, defined as a >= 25% decline in PSA within 4-6 week of stopping a nonsteroidal antiandrogen, are not eligible until the PSA rises above the nadir observed after antiandrogen withdrawal\r\n* Patients must have a castrate serum level of testosterone (< 50 ng/dL) within 6 weeks of day 1
Androgen receptor positivity, defined as >= 10% of tumor cell nuclei with immunoreactivity for AR on central review at Vanderbilt
Participation in a previous clinical trial of enzalutamide or an investigational agent that inhibits the androgen receptor (ARN-509) or androgen synthesis
Patients progressing on LHRH agonist plus an anti-androgen as first line therapy must be off anti-androgen for 4 weeks prior to first treatment with testosterone
Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation is =< 60 days prior to the date of registration
Use of any medications known to affect the serum androgen level
Tumor with androgen receptor (AR) expressed >= 4580 copies/ug ribonucleic acid (RNA)
Patient has any prior use of anti-androgen therapies.
Progression on a prior regimen/line of an androgen synthesis inhibitor for prostate cancer
Prior treatment with enzalutamide or any other newer hormonal androgen receptor inhibitor (e.g., apalutamide, ODM-201)
Current treatment with anti-androgen is allowed for a maximum of one month to prevent flare response with ADT
No ongoing anti-androgen therapy; patients must be off anti-androgen therapy for at least 30 days
Prior treatment with: second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, or CYP17 enzyme inhibitor.
Specific eligibility criteria for Part 2 CRPC expansion cohort: Persistent disease with evidence of disease progression following standard therapy(ies) including prior treatment with androgen/androgen receptor directed therapy, including enzalutamide and/or abiraterone
Androgen suppression or anti-androgen therapy within the 12 months prior to dosing, for prostate cancer.
Anti-androgen receptor antagonist therapy must be bicalutamide. Subjects already started on other anti-androgens must be willing to switch over to bicalutamide.
Experienced disease progression after having received 1 prior next generation androgen receptor-targeted therapy for castration-resistant disease
Androgen receptor positive (AR+)\r\n* Defined as >= 10% nuclear AR staining by immunohistochemistry (IHC) in either the primary or metastatic lesion\r\n* NOTE: Research testing of AR status is available at City of Hope (COH) Pathology
For participants previously treated with first generation anti-androgens (ie, flutamide, nilutamide, or bicalutamide), discontinuation of flutamide or nilutamide therapy must occur greater than (>) 4 weeks (>6 weeks for bicalutamide) prior to start of study drug with no evidence of an anti-androgen withdrawal response (no decline in serum PSA)
Started less than 12 weeks prior to randomisation AND Prostate Specific Antigen (PSA) is stable or falling. The 12 weeks starts from whichever of the following occurs earliest: first dose of oral anti- androgen, LHRHA, or surgical castration.
Patients who have received TOK-001 (Galeterone®) or any other investigational product directed towards the androgen receptor or androgen biosynthesis.
Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) as part of their first-line hormonal therapy must have shown progression of disease off the anti-androgen prior to enrollment
At least 4 weeks must have elapsed from the use of androgen receptor antagonists (e.g., bicalutamide, flutamide, nilutamide); 5-alpha reductase inhibitors (e.g., dutasteride, finasteride, aminoglutethimide); estrogens; ketoconazole and other anti-cancer pharmacologic therapy prior to enrollment
At least 6 weeks must have elapsed from the use of bicalutamide if used as part of an initial combined androgen blockage therapy for more than 6 months or if used as second line hormonal therapy and associated with a PSA response of at least 3 months duration
Patients who are receiving an anti-androgen as part of their first-line hormonal therapy must have shown progression of disease off the anti-androgen prior to enrollment
At least 4 weeks must have elapsed from the use of androgen receptor antagonists (i.e., flutamide, nilutamide, bicalutamide, enzalutamide); 5-alpha (a) reductase inhibitors (i.e., finasteride, aminoglutethimide); abiraterone acetate; estrogens; nitrosoureas, mitomycin C, isotype therapy, ketoconazole, chemotherapy and other anti-cancer pharmacologic therapy prior to beginning protocol therapy
Prior use, or participation in a clinical trial, of an investigational agent that blocks androgen synthesis (e.g., abiraterone acetate, TAK-700, TAK-683, TAK-448) or agents that block the androgen receptor (e.g., ARN-509)
Subjects who received combined androgen blockade with an anti-androgen must have shown PSA(prostate specific antigen) progression after discontinuing the anti-androgen prior to enrollment.
Prior participation in a clinical trial of an investigational agent that inhibits the androgen receptor or androgen synthesis (unless the treatment was placebo)
Previous anti-androgen therapy and progression after withdrawal; patients who received combined androgen blockade with an anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to enrollment (>= 4 weeks since last flutamide, >= 6 weeks since last bicalutamide or nilutamide)
No treatment with any of the following for prostate cancer within 4 weeks prior to enrollment:\r\n* Hormonal therapy (e.g., androgen receptor [AR] antagonists, 5 alpha reductase inhibitors, estrogens); Note: treatment with bicalutamide and nilutamide within 4 weeks prior to enrollment is not allowed; treatment with flutamide within 4 weeks prior to enrollment is not allowed; treatment with all other gonadotropin-releasing hormone (GnRH) analogues or antagonists is allowed\r\n* Chemotherapy\r\n* Biologic therapy\r\n* Investigational therapy\r\n* Immunotherapy
No prior anti-androgen therapy (bicalutamide, flutamide or nilutamide) is permitted
Patients who have received androgen ablative therapy for less than 8 weeks immediately prior to initiation of study drug are eligible provided they had only PSA evidence of progression (as defined above) with no visible metastases by CT-scan and bone scan (within 6 weeks) prior to starting androgen ablation
Demonstration of progression while on androgen blockade
Castrate-resistant disease, defined as follows:\r\n* All patients must have received standard of care androgen deprivation treatment before trial entry (surgical castration versus gonadotropin-releasing hormone [GnRH] analogue or antagonist treatment), and subjects receiving GnRH analogue or antagonist must continue this treatment throughout the time on this study\r\n* Patients may have been treated previously with a nonsteroidal antiandrogen, with evidence of disease progression subsequently; subjects must be off use of anti-androgen for at least 4 weeks (for flutamide) or 6 weeks (for bicalutamide or nilutamide) prior to registration\r\n** Subjects who demonstrate an anti-androgen withdrawal response, defined as a >= 25% decline in PSA within 4-6 week of stopping a nonsteroidal antiandrogen are not eligible until the PSA rises above the nadir observed after antiandrogen withdrawal\r\n* Castration levels of testosterone (< 50 ng/dL) within 2 weeks of registration
If a patient enters the trial on androgen suppression therapy (AST) that consists of both an LHRH agonist and an oral antiandrogen, both agents should be continued throughout the study; if an antiandrogen is stopped prior to study entry, it should be stopped 4 weeks before for nilutamide and flutamide and 6 weeks before for bicalutamide to ensure that a withdrawal phenomenon does not interfere with interpretation of efficacy results
For patients who have been on anti-androgen therapy and had evidence of response to the addition of an anti-androgen (i.e., PSA reduction), patients must have discontinued anti-androgen therapy for at least six weeks (4 weeks for flutamide) without current evidence of an anti-androgen withdrawal response
For patients previously treated with first generation anti-androgens (i.e., flutamide, nilutamide, or bicalutamide), discontinuation of flutamide or nilutamide therapy must occur >4 weeks (>6 weeks for bicalutamide) prior to start of study drug with no evidence of an anti-androgen withdrawal response (i.e., no decline in serum PSA).
Prior treatment with investigative androgen receptor (AR) agents
Subjects must have discontinued additional hormonal (eg bicalutamide, abiraterone, estrogen) therapy prior to the first dose of cabozantinib; no anti-androgen withdrawal period is required
Androgen receptor expression testing confirms that the patient’s tumor is AR (+); AR is considered positive if >= 1% of cell nuclei are immunoreactive using the Dako antibody (clone androgen receptor antibody [AR441]); receptor testing may be performed on either primary tumor specimen or tissue from a metastatic site; local testing permitted for eligibility but will require confirmation at Memorial Sloan-Kettering Cancer Center (MSKCC)
Patients who have received prior anti-androgen therapy
Prior investigational new generation potent anti-androgen therapy (such as ARN 509).
Prior progression on one or more androgen-receptor/androgen-synthesis inhibitor therapies (e.g. abiraterone, enzalutamide, apalutamide, TAK-700 and/or galeterone) by Prostate Cancer Working Group 2 (PCWG2) criteria. Prior progression on bicalutamide/nilutamide/flutamide/ketoconazole alone is not allowed.
Use of a first-generation anti-androgen such as bicalutamide within 6 weeks of study drug dosing, or flutamide within 4 weeks of study dosing
Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide), 5-? reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or biologic therapy within 4 weeks of Day 1 visit
Prior therapy with other CYP17 inhibitor(s) or investigational agent(s) targeting the androgen receptor for metastatic prostate cancer
Concurrent anti-androgen therapy
Previous anti-androgen therapy and progression after withdrawal
Patient must have evidence of castration resistant prostate cancer as evidenced by a confirmed rising PSA (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a castrate serum testosterone level (i.e. =< 50 mg/dL); if a subject also received an anti-androgen, he must first progress through antiandrogen withdrawal prior to being eligible; the minimum timeframe to document failure of anti-androgen withdrawal will be four weeks
Patients, who have experienced disease progression despite initial hormonal therapy, either by orchiectomy or by using a gonadotropin-releasing hormone (GnRH) agonist in combination with an anti-androgen, must first progress through anti-androgen withdrawal prior to being eligible; the minimum timeframe to document failure of anti-androgen withdrawal will be four weeks; patients on second-line (or beyond) hormonal maneuvers, and patients who had no PSA decline on combined androgen blockade as first line therapy, need not progress through anti-androgen withdrawal (AAW) in order to be eligible
Previous androgen blockade (e.g. antiandrogens) given for greater than 2 weeks in the last 3 months; anti-androgens used during the initiation of ADT to avoid a flare phenomenon are acceptable for up to 4 weeks
Other investigational agents in addition to LHRH agonist/antagonist are allowed (e.g. novel anti-androgens, androgen synthesis inhibitors)
Have received prior investigational anti-androgen therapy, including ARN-509
Patients on long term (> 6 months) anti-androgen therapy (e.g. flutamide, bicalutamide, nilutamide) will need to be off anti-androgen for 4 weeks (wash out period) and show evidence of disease progression off the anti-androgen; patients that have been on an anti-androgen 6 months or less will need to discontinue anti-androgen therapy prior to treatment start (no wash out period required)
Be planning to begin a course of at least 4 months of ADT; the ADT is defined as: (a) surgical castration; (b) gonadotropin-releasing hormone (GNRH) antagonist alone; (c) GNRH antagonist with oral androgen receptor blockade, and (d) GNRH antagonist, oral androgen receptor blockade, and 5-alpha reductase inhibitors; we will not include men with only oral anti-androgen therapy such as 5-alpha reductase inhibitors alone or oral anti-androgens alone
Androgen ablation (hormone treatment) within the last 3 months
Physician prescription of androgen receptor antagonist therapy (examples: bicalutamide, flutamide, or enzalutamide) during time of protocol scans
Use of any medications known to affect the serum androgen levels or the PSA