Any prior chemotherapy or androgen receptor (AR)-directed therapy for CRPC, (e.g. docetaxel, cabazitaxel, mitoxantrone, abiraterone acetate, ketoconazole, or enzalutamide); previous treatment with radium- or sipuleucel-T is allowed
Prior exposure to enzalutamide or other investigational AR directed therapy
Any prior therapy for castrate disease is acceptable except prior specific cytochrome P family  (CYP) antagonists (e.g. abiraterone acetate, orteronel) or prior second generation AR antagonists (e.g. enzalutamide or ARN) which are excluded; a minimum washout of  days for any other anticancer therapy (with the exception of sipuleucel-T, which does not need a wash out) prior to first dose of study drug is required
Prostate cancer patients must have received and progressed on enzalutamide
Prior exposure to enzalutamide, ARN-, or other investigational androgen receptor (AR)-directed therapy
Currently on abiraterone and/or enzalutamide and not progressing; OR
Pre-abiraterone and pre-enzalutamide with demonstrated evidence of progressive disease. Defined as at least one of the following:
Previous progression (radiographic or PSA progression) while on treatment with abiraterone, enzalutamide, or a combination.
Patients may not have received enzalutamide or ARN- (another androgen receptor antagonist) in the past
In Stage , patients may or may not have received prior chemotherapy for mCRPC. In Stage , patients will be enrolled into two cohorts based on whether or not they have received prior chemotherapy for mCRPC. Any prior chemotherapy must have been completed ?  weeks prior to administration of ES. Additionally, in countries where abiraterone or enzalutamide are commercially available, patients in Stage  and  must have progressed on abiraterone and/or enzalutamide prior to study entry.
Any chemotherapy, sipuleucel-T, or investigational drug in prior  weeks, or abiraterone or enzalutamide in prior  week
previously treated with abiraterone, enzalutamide alone or in combination AND must have demonstrated evidence of objective progression as per PCWG criteria
Prior treatment with enzalutamide for CPRC; non-CRPC use is allowed (e.g., neoadjuvant, combined with radiation for localized disease and didnt progress while on it in those settings)
Must have received at least  line of AR-targeted therapy or androgen bio-synthesis inhibitor (e.g., abiraterone acetate, enzalutamide, apalutamide) for prostate cancer (PCa)
Prior treatment with CYP inhibitor (e.g. ketoconazole, abiraterone acetate, galeterone) or second generation androgen receptor antagonist including apalutamide or enzalutamide
No prior treatment with enzalutamide, ARN-, ODM-, galeterone or other investigational androgen receptor (AR) targeted treatment is allowed
Prior treatment with enzalutamide is prohibited
Prior treatment with enzalutamide or other potent androgen-receptor blockers, approved or experimental (e.g., ARN-, ODM-, or galeterone)
Prior abiraterone and enzalutamide are permitted, but not required
Patients physician has already recommended enzalutamide for treatment of progression
Previous treatment with an agent that blocks adrenal androgen synthesis (e.g. abiraterone acetate, TAK-, TOK-, ketoconazole) or second generation androgen receptor (AR) antagonists (e.g., BMS , ARN-,TOK-)
Previous treatment with enzalutamide (MDV)
Patients must have discontinued enzalutamide at least  days prior to enrollment.
Patients must have received treatment with prior enzalutamide for greater than three -day cycles and must have had evidence of disease progression while on enzalutamide.
Prior treatments with TAK-/Orteronel, abiraterone, ketoconazole, or enzalutamide
Prior enzalutamide and/or abiraterone treatment is allowed
Treatment failure of either abiraterone and/or enzalutamide as evidenced by a confirmed rising PSA (per PCWG criteria) and a castrate serum testosterone level (i.e. =<  mg/dL) while receiving treatment with either abiraterone and/or enzalutamide
Current systemic therapy (other than a gonadotrophin releasing hormone [GnRH] agonist/antagonist) for CRPC including:\r\n* CYP- inhibitors (e.g. ketoconazole, abiraterone)\r\n* Antiandrogens (e.g. bicalutamide, nilutamide)\r\n* Second generation antiandrogens (e.g. enzalutamide, ARN-, Galeterone)\r\n* Immunotherapy (e.g. sipuleucel-T, ipilimumab)\r\n* Chemotherapy (e.g. docetaxel, cabazitaxel)
Adequate baseline organ function within  days prior to the first dose of enzalutamide and/or CORT
If a patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for  days after completing treatment with CORT or enzalutamide. A condom is required during and for  days after completing treatment with enzalutamide if a patient is engaged in sexual activity with a pregnant woman. Patients must also agree to avoid sperm donation during the study and for at least  days after the final treatment administration.
Cohort B: Patients must have progressed during treatment with enzalutamide or second-generation AR-blocking therapies. Patients progressing on enzalutamide immediately prior to enrolling in this study must be on stable doses of enzalutamide  mg once daily (QD). These patients will continue enzalutamide without interruption during the screening period (no wash-out period required).
Received prior treatment with enzalutamide, or
Ongoing or anticipated therapy with hormone therapy (other than LHRH antagonist), including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) or received abiraterone within  days prior to the first dose of enzalutamide and/or CORT
Prior exposure to ketoconazole (systemic), abiraterone acetate, enzalutamide or other agents targeting the androgen receptor (AR) signaling pathway
Previously treated with enzalutamide or experimental therapies directed against androgen receptor (ie, apalutamide).
Prior treatment with: LHRH agonist/antagonists; second generation androgen receptor (AR) inhibitors such as enzalutamide, ARN-, darolutamide (ODM-); other investigational AR inhibitors; CYP enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer, chemotherapy or immunotherapy for prostate cancer prior to randomization.
Prior use of ketoconazloe, enzalutamide, abiraterone or apalutamide or participation in a previous clinical trial of ketoconazloe,enzalutamide, abiraterone or apalutamide
Previous investigational antiandrogens (e.g., apalutamide, enzalutamide, BMS-).
Have received prior abiraterone and/or enzalutamide
No prior therapy with AR antagonists including but not limited to bicalutamide, enzalutamide, abiraterone and orteronel.
Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g. abiraterone, orteronel) in the past  months; -alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as long as subject has been stable on medication for past  months
Patients enrolling in this trail should have received either Enzalutamide or Abiraterone
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 >=  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
Subjects must have received, were ineligible to receive, or refused at least one cytotoxic chemotherapy and enzalutamide or abiraterone or both enzalutamide and abiraterone
Prior exposure to enzalutamide, androgen receptor antagonist ARN- (ARN-) or other investigational AR-directed therapy in the setting of mCRPC
Antiandrogens (e.g., bicalutamide, flutamide, nilutamide, abiraterone, enzalutamide) for >  months prior to consenting; patients on -alpha reductase inhibitors are allowed on study
Prior therapy with second line hormonal therapy is allowed (i.e. bicalutamide, nilutamide, flutamide, ketoconazole, abiraterone, enzalutamide, ARN-)
A minimum of  weeks off of enzalutamide or abiraterone, if applicable, prior to registration
Prior treatment with an anti-androgen (abiraterone, apalutamide [ARN-], bicalutamide, enzalutamide, AR antagonist ODM- [ODM-], TAK-, TAK-, orteronel [TAK-], seviteronel [VT-])
Prior treatment with an anti-androgen (abiraterone, ARN-, bicalutamide, enzalutamide, ODM-, TAK-, TAK-, TAK-, VT-)
Patient has received enzalutamide for the treatment of prostate cancer; however, previous treatment with other hormonal therapy (bicalutamide, abiraterone, ketoconazole, flutamide, and nilutamide) or chemotherapy (docetaxel, cabazitaxel, or mitoxantrone) is allowed
Prior or ongoing systemic therapy for prostate cancer including, but not limited to:\r\n* Hormonal therapy (for example [e.g.] leuprolide, goserelin, triptorelin, degarelix)\r\n* Cytochrome P (CYP)- inhibitors (e.g. ketoconazole)\r\n* Antiandrogens (e.g. bicalutamide, nilutamide)\r\n* Second generation antiandrogens (e.g. enzalutamide, apalutamide)\r\n* Immunotherapy (e.g. sipuleucel-T, ipilimumab)\r\n* Chemotherapy (e.g. docetaxel, cabazitaxel)
Prior enzalutamide, abiraterone or ketoconazole
Histologically confirmed metastatic castrate resistant cancer (mCRPC) who progressed after both hormonal therapy (abiraterone or enzalutamide) and chemotherapy (docetaxel, for example); or cannot tolerate either or both of these classes of therapies.
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-V
Patient has received niclosamide, abiraterone or ketoconazole for the treatment of prostate cancer; however, previous treatment with other hormonal therapy (bicalutamide, enzalutamide, flutamide and nilutamide) or chemotherapy (docetaxel, cabazitaxel or mitoxantrone) is allowed
Prior or ongoing systemic therapy for prostate cancer including, but not limited to:\r\n* Hormonal therapy (e.g. leuprolide, goserelin, triptorelin)\r\n* Cytochrome P (CYP)- inhibitors (e.g. abiraterone, ketoconazole)\r\n* Antiandrogens (e.g. bicalutamide, nilutamide)\r\n* Second generation antiandrogens (e.g. enzalutamide)\r\n* Immunotherapy (e.g. sipuleucel-T, ipilimumab)\r\n* Chemotherapy (e.g. docetaxel, cabazitaxel)
Treatment within  months of cycle  day  with any Cyp-lyase inhibitor, any nd generation AR antagonist (e.g. enzalutamide), cabazitaxel or carboplatin
Patients treated with any Cyp-lyase inhibitor, any nd generation AR antagonist (e.g. enzalutamide), cabazitaxel or carboplatin whose disease progressed while on treatment or within  months of its discontinuation; patients who have received any of these treatments more than  months from study entry and whose disease did not progress while on treatment or within  months of its discontinuation are allowed on study
SECOND COHORT: The most recent therapy must be enzalutamide and enzalutamide will be continued for study duration despite progressive disease; the minimum required dose of enzalutamide at enrolment should be no less than  mg once daily
SECOND COHORT: Concurrent therapy with enzalutamide will be permitted and is a requirement for enrollment
Prior treatment with abiraterone or enzalutamide is permitted, but patients must have been off prior corticosteroid treatment for at least  months
Prior treatment with anti-androgens other than enzalutamide is acceptable
Prior treatment with enzalutamide
Have had prior enzalutamide, ARN-, or galeterone therapy
There must be no plans for the patient to receive other concomitant or post treatment adjuvant antineoplastic therapy while on this protocol including surgery, cryotherapy, conventionally fractionated radiotherapy, nd generation anti-androgen therapy (i.e. enzalutamide, abiraterone, etc.), or chemotherapy given as part of the treatment of prostate cancer
For Cohort C (castration-only):\r\n* Patients must continue on castrating therapy throughout BAT treatment\r\n* No prior second line hormone treatment with flutamide, bicalutamide, nilutamide, enzalutamide, abiraterone, ketoconazole, ARN- or other investigational androgen ablative therapies is permitted for Cohort C
Prior treatment with abiraterone acetate, enzalutamide, apalutamide (ARN-), galeterone (TOK-), orteronel (TAK-), or similar agent
Must have previously received at least , but no more than , lines of novel androgen receptor (AR)-targeted therapy (for example, abiraterone acetate with prednisone, enzalutamide, apalutamide) for prostate cancer. Participants must have had at least  weeks of AR-targeted therapy
Any approved or investigational agent that blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, ARN-, bicalutamide, enzalutamide, ODM-, TAK-, TAK-, TAK-)
Patients must have progressed on abiraterone and/or enzalutamide; there must be at least a -week washout period after stopping the most recent approved therapy for mCRPC (i.e., abiraterone, enzalutamide, Ra-, sipuleucel-t); if applicable, patients should be weaned off steroids at least  week prior to starting treatment
No prior abiraterone acetate, enzalutamide or apalutamide or other novel AR or CYP antagonist, or docetaxel for castration resistant prostate cancer; if used for hormone nave disease, last dose was at least  months prior to randomization
Prior treatment with ARN- or enzalutamide (there is a grace period for men who wish to enroll and who have recently started enzalutamide for the first time but have taken less than  days of therapy)\r\n* Concurrent use of androgen deprivation therapy aside from LHRH agonist or antagonist (i.e. bicalutamide, flutamide, nilutamide, abiraterone, ketoconazole, estrogen); there will be a  week wash-out period from the last dose of any of these agents until the first dose of enzalutamide on study; patients who have just started enzalutamide for fewer than  doses prior to enrollment in the trial are still considered eligible and not subject to wash-out
Expression of AR-V is not required as expression of AR-V can occur during enzalutamide and contribute to resistance to enzalutamide
Patient has received enzalutamide for the treatment of prostate cancer; however, previous treatment with other hormonal therapy (bicalutamide, flutamide, nilutamide, abiraterone and ketoconazole) or chemotherapy (docetaxel, cabazitaxel or mitoxantrone) is allowed
No prior therapy with enzalutamide (previous chemotherapy and/or other AR-targeted approaches is allowed)
Subjects must have failed prior therapy with abiraterone, enzalutamide, or both: has completed at least  weeks of prior continuous therapy with abiraterone or enzalutamide; has not been without abiraterone or enzalutamide treatment for > days prior to initiation of study treatment; lead-in dosing period for enzalutamide only will be required under the following circumstance:
If the subject has enzalutamide discontinuation for > days prior to dosing start with GSK plus enzalutamide on trial, then a enzalutamide only lead-in dosing of  days is required
If the subject has enzalutamide discontinuation for <= days prior to dosing start with GSK plus enzalutamide on trial, then a enzalutamide only lead-in dosing of  days is required
If the subject is on continuous dosing with enzalutamide prior to dosing start with GSK plus enzalutamide on trial, then subject can start on combined dosing at end of screening period; Lead-in dosing period for abiraterone only will be required: if the subject has abiraterone discontinuation for more than  days prior to dosing start with GSK plus abiraterone on trial, then abiraterone only lead-in dosing of  days is required.
Recent prior therapy, defined as: Any investigational or approved non-biologic anti-cancer drug (see exception below) within  days prior to the first dose of GSK and abiraterone/enzalutamide. Exception: For allowed androgen deprivation therapy (hormonal, abiraterone, enzalutamide. Concomitant prednisone (or equivalent) allowed in combination with abiraterone dosing, any nitrosoureas or mitomycin C within  days prior to the first dose of GSK and abiraterone/enzalutamide, any anti-cancer biologic agents within five half-lives prior to the first dose of GSK and abiraterone/enzalutamide, if the subject received radiotherapy < days prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response. Exception: Any radiotherapy within  days prior to the first dose of GSK and abiraterone/enzalutamide must be limited to a single fraction of radiotherapy for the purpose of palliation (confined to one field) is permitted, any major surgery within  days prior to the first dose of GSK and abiraterone/enzalutamide
Prior treatment with enzalutamide or any other newer hormonal androgen receptor inhibitor (e.g., apalutamide, ODM-)
Prior use of enzalutamide
Prior treatment with other second line hormone therapy is allowed (e.g. flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, ARN-); patients must be off these therapies for at least  weeks prior to starting treatment
Disease progression according to Prostate Cancer Working Group  (PCWG) criteria during or following treatment with an androgen pathway inhibitor (that is, enzalutamide, abiraterone) for metastatic CRPC
Subjects must have received abiraterone and/or enzalutamide. Subject must have received either abiraterone or enzalutamide for ? weeks. Other second generation CYP inhibitors/androgen receptor antagonists including but not limited to TAK- (orteronel), TOK- (galeterone) may have been taken in place of abiraterone and ARN- (apalutamide) may have been taken in place of enzalutamide.
Subject received prior aminoglutethimide, ketoconazole, abiraterone acetate or enzalutamide for the treatment of prostate cancer or participation in a clinical study of an investigational agent that inhibits the AR or androgen synthesis (e.g., TAK-, ARN-, ODM-).
Patients must have progressed on abiraterone and/or enzalutamide.
For inclusion in Cohort , mCRPC patients must have progressed while receiving (or subsequent to receiving) abiraterone and/or enzalutamide but must not have previously received taxane-based systemic chemotherapy for mCRPC (previous treatment with six cycles of docetaxel for metastatic castration-sensitive prostate cancer (mCSPC) is permissible). NOTE: patients receiving fewer than  cycles of taxane based regimen due to intolerance are eligible for cohort .
For inclusion in Cohort , mCRPC patients must have progressed while receiving (or subsequent to receiving) abiraterone and/or enzalutamide and must have progressed subsequent to receiving ?  cycles of a taxane-based regimen for mCRPC.
Has discontinued antiandrogens (bicalutamide, nilutamide) > weeks and enzalutamide > weeks prior to Day  of trial treatment
AR targeted agents (including GTx-, enzalutamide or other AR targeted therapies)
Received double-blind enzalutamide study treatment during the main study.
Subject has received an agent that either blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, bicalutamide, enzalutamide, ARN- or other investigational AR signaling inhibitors). The exception of spironolactone is allowed after Medical Monitor consultation.
Prior enzalutamide, abiraterone acetate, aminoglutethimide, ketoconazole, radium Ra  dichloride or other bone-targeting radionuclides, or cytotoxic chemotherapy in the CRPC setting for the treatment of prostate cancer or participation in a clinical trial of an investigational agent that inhibits the androgen receptor or androgen synthesis (unless treatment was placebo);
ENTRY CRITERIA: Metastatic, castration resistant prostate cancer progressing on enzalutamide after initial response to enzalutamide
Has allergy to enzalutamide
No limit on number or type of prior therapies\r\n* Prior treatment with docetaxel is permitted but not required\r\n* Prior treatment with ketoconazole, estrogens, abiraterone or novel antiandrogens allowed, including past enzalutamide\r\n* Require at least a  week withdrawal period from the last dose of bicalutamide, or nilutamide or  weeks from last flutamide or enzalutamide dose\r\n** Must have a documented PSA rise after stopping the antiandrogen\r\n* Will require a  week washout period from last dose of ketoconazole, chemotherapy, radiation (including radium-), or prior investigational systemic agents
Prior treatment with enzalutamide
Patients must have received treatment with either enzalutamide and/or abiraterone prior to study entry
At least  weeks must have elapsed from the use of androgen receptor antagonists (i.e., flutamide, nilutamide, bicalutamide, enzalutamide); -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
Previous enzalutamide therapy
Previous use, or participation in a clinical trial, of an investigational agent that blocks androgen synthesis (e.g., abiraterone acetate, TAK-, TAK-, TAK-) or targets the androgen receptor (e.g., enzalutamide, BMS ); ketoconazole
Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone, or enzalutamide for the treatment of prostate cancer
Previous exposure to any nd generation anti-hormonal including abiraterone and enzalutamide
No prior enzalutamide, abiraterone, or other novel antiandrogen or androgen synthesis inhibitor
Prior treatment with enzalutamide
Prior treatment with enzalutamide, TOK-, or ARN-; prior therapy with abiraterone or orteronel is permitted, but must have been stopped a minimum of two weeks prior to study entry; prior and/or concurrent treatment with bone-targeted therapy such as bisphosphonates or denosumab is permitted
Prior treatment with CYP inhibitors or AR antagonists (e.g. abiraterone, TAK-, ARN-, ketoconazole*, enzalutamide, or galeterone) - Treatment nave only
Prior treatment with CYP inhibitors (e.g. TAK-, ketoconazole*) or AR antagonists (e.g. enzalutamide, ARN-,) or galeterone - abiraterone refractory only
Prior treatment with CYP inhibitors (e.g. abiraterone, TAK-, ketoconazole*) or AR antagonists (e.g. ARN -) or galeterone - enzalutamide refractory only
Patients enrolled on the randomized portion of the study must have had disease progression on abiraterone or enzalutamide
Has taken commercially available enzalutamide (Xtandi);
Must have received at least  prior therapies approved for CRPC; including a prior AR inhibitor (e.g., enzalutamide or apalutamide). (Part  only)
Must have received enzalutamide or apalutamide. (Note: additional therapies approved for CRPC prior to enzalutamide or apalutamide are allowed.) (Part  only)
Patients with rapidly progressive disease who are candidates for other approved therapies such as docetaxel, abiraterone, and enzalutamide.
Prior therapy with abiraterone, orteronel, ketoconazole, or any other Cytochrome P (CYP)  lyase inhibitor; enzalutamide or other experimental androgen receptor antagonist; or experimental immunotherapy agent.
Prior treatment with any anti-androgens, including but not limited to, enzalutamide and bicalutamide
Demonstrated progression on abiraterone and/or enzalutamide
Received more than one treatment course of enzalutamide or abiraterone
Subject has been previously treated with enzalutamide for at least  months, and stopped enzalutamide due to progressive disease (not due to adverse events), followed by at least  cycles of docetaxel and/or cabazitaxel chemotherapy, with or without other intervening anti-cancer therapies (including but not limited to aminoglutethimide, ketoconozole, abiraterone acetate, Rad-, or sipuleucel-T), prior to receiving chemotherapy. Note: for patients who receive sequential taxanes, there must not have been progressive disease upon ending the first taxane, or use of any anti-cancer agents between the two taxanes.
Prior treatment with second generation anti-androgens (e.g. abiraterone, enzalutamide)
Must have received at lease one agent known to impact survival (abiraterone, enzalutamide, ect.)
Prior abiraterone and enzalutamide are permitted ( week washout for both agents)
CRPC subjects: Must have measurable disease by either: RECIST. or a minimum PSA of  nanogram/milliliter; Disease progression on last line of therapy and must have progressed on abiraterone, enzalutamide, or taxane chemotherapy; Subjects may continue GnRH agonists; Small cell prostate cancer is eligible
Prior treatment with enzalutamide.
PHASE II  GROUP B: Progressive disease must have occurred on abiraterone within the prior  months and patient has not received treatment with enzalutamide
Ongoing systemic therapy (other than a GnRH agonist/antagonist) for prostate cancer including, but not limited to:\r\n* CYP- inhibitors (e.g. ketoconazole, abiraterone)\r\n* Antiandrogens (e.g. bicalutamide, nilutamide)\r\n* Second generation antiandrogens (e.g. enzalutamide)\r\n* Immunotherapy (e.g. sipuleucel-T, ipilimumab)\r\n* Chemotherapy (e.g. docetaxel, cabazitaxel)\r\nNote: Prior receipt of these agents is acceptable; no washout period is required
Patients who have had prior sipuleucel-T, docetaxel, cabazitaxel, abiraterone or enzalutamide as a single agent, or in combination therapy
Administration of any investigational drug within  days prior to receipt of enzalutamide, abiraterone, prednisone or denosumab
Prior progression on one or more androgen-receptor/androgen-synthesis inhibitor therapies (e.g. abiraterone, enzalutamide, apalutamide, TAK- and/or galeterone) by Prostate Cancer Working Group  (PCWG) criteria. Prior progression on bicalutamide/nilutamide/flutamide/ketoconazole alone is not allowed.
Patient must be eligible for treatment with enzalutamide
Ongoing systemic therapy (other than a gonadotropin releasing hormone [GnRH] agonist/antagonist) for prostate cancer including, but not limited to:\r\n* Cytochrome P, family  (CYP-) inhibitors (e.g. ketoconazole, abiraterone)\r\n* Antiandrogens (e.g. bicalutamide, nilutamide)\r\n* Second generation antiandrogens (e.g. ARN-)\r\n** Note: patients receiving ongoing treatment with enzalutamide will be allowed to join the study\r\n* Immunotherapy (e.g. sipuleucel-T, ipilimumab)\r\n* Chemotherapy (e.g. docetaxel, cabazitaxel)\r\n* Radiopharmaceutical therapy (e.g. radium-, strontium-, samarium-)
Enzalutamide; primary resistance to enzalutamide will be defined as:\r\n* No PSA decline\r\n* PSA decline less than % after  weeks of enzalutamide therapy\r\n* PSA progression within  weeks of enzalutamide treatment (by PCWG criteria), after initial response to therapy\r\n* Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG criteria for bone lesions within  weeks of starting enzalutamide treatment\r\n* Unequivocal clinical progression (per the treating provider's discretion) within  weeks of starting enzalutamide treatment
Other second-generation investigational anti-androgen/androgen-receptor targeted therapies, including apalutamide (ARN-); primary resistance will be defined as:\r\n* No PSA decline\r\n* PSA decline less than % after  weeks of enzalutamide therapy\r\n* PSA progression within  weeks of enzalutamide treatment (by PCWG criteria), after initial response to therapy\r\n* Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG criteria for bone lesions within  weeks of starting enzalutamide treatment\r\n* Unequivocal clinical progression (per the treating provider's discretion) within  weeks of starting enzalutamide treatment
Combination therapy with abiraterone, enzalutamide and/or other second- generation investigational anti-androgen/androgen-receptor targeted therapies, including ARN-; primary resistance to combination therapy will be defined as:\r\n* No PSA decline\r\n* PSA decline less than % after  weeks of abiraterone and enzalutamide therapy\r\n* PSA progression within  weeks of abiraterone and enzalutamide treatment (by PCWG criteria), after initial response to therapy\r\n* Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG criteria for bone lesions within  weeks of starting abiraterone and enzalutamide treatment\r\n* Unequivocal clinical progression (per the treating providers discretion) within  weeks of starting abiraterone and enzalutamide treatment
Sequenced therapy, including any of the following:\r\n* Abiraterone acetate followed by enzalutamide\r\n** Primary resistance will be defined per criteria for abiraterone monotherapy primary resistance\r\n* Enzalutamide followed by abiraterone acetate\r\n** Primary resistance will be defined per criteria for enzalutamide monotherapy primary resistance\r\n* Other second-generation investigational anti-androgen/androgen- receptor targeted therapies, including ARN-\r\n** Primary resistance will be defined per criteria for other investigational anti-androgen monotherapy primary resistance
Discontinuation of prior therapy for mCRPC: a washout period of  days for the following therapies is required: abiraterone, enzalutamide, fluconazole, itraconazole, flutamide, bicalutamide, nilutamide, and other experimental hormonal agents (ARN, orteronel [TAK-], etc.), sipuleucel-T (Provenge), other experimental vaccines (PROSTVAC-V/F, etc.), strontium-, samarium, and radium- chloride
Completed at least  weeks of prior continuous therapy with enzalutamide. A  week or less treatment (enzalutamide) holiday will be permitted prior to initiating study treatment.
Investigational therapy other than enzalutamide.
Additional ADT agents may be concurrently administered (abiraterone, bicalutamide, enzalutamide, etc.)
Dose Escalation only: Enzalutamide-nave patients following prior progression on abiraterone by PCWG criteria and within  weeks of discontinuing abiraterone
Dose Confirmation Cohort B (DC-B) only: Enzalutamide-nave patients following prior progression on abiraterone by PCWG criteria and within  weeks of discontinuing abiraterone
Initiated therapy with either abiraterone plus a glucocorticoid or enzalutamide within the  months prior to randomization
Currently receiving or history of systemic therapy with testosterone suppressing medication (i.e., lupron, degarelix, abiraterone, enzalutamide) or local radiation therapy.
Planned or ongoing treatment with an androgen signaling inhibitor (e.g., abiraterone, enzalutamide, ARN-) or another systemic therapy for mCRPC
Patients starting abiraterone or starting enzalutamide ), within approximately - days of baseline F-DCFPyL PET/CT
Physician prescription of androgen receptor antagonist therapy (examples: bicalutamide, flutamide, or enzalutamide) during time of protocol scans
Prior use of degarelix, enzalutamide, trametinib, or dasatinib in any context
Patients must not be on enzalutamide within five half-lives before the first planned dose of the study drug or anticipating to start enzalutamide within the next  months of the first planned dose of study drug