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-223 or sipuleucel-T is allowed
Prior exposure to abiraterone acetate or other specific cytochrome P450 (CYP)-17 inhibitors; abiraterone acetate given in the castration-sensitive setting is permissible if stopped at least 6 months prior to initial protocol treatment
Prior exposure to enzalutamide or other investigational AR directed therapy
Any prior therapy for castrate disease is acceptable except prior specific cytochrome P450 family 17 (CYP17) antagonists (e.g. abiraterone acetate, orteronel) or prior second generation AR antagonists (e.g. enzalutamide or ARN509) which are excluded; a minimum washout of 28 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
May have received treatment with abiraterone acetate, enzalutamide and/or one prior chemotherapy (docetaxel)
Prior exposure to abiraterone acetate, ketoconazole or other specific cytochrome (CYP)-17 inhibitors
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.
In Stage 1, patients may or may not have received prior chemotherapy for mCRPC. In Stage 2, 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 ? 4 weeks prior to administration of ES414. Additionally, in countries where abiraterone or enzalutamide are commercially available, patients in Stage 1 and 2 must have progressed on abiraterone and/or enzalutamide prior to study entry.
Any chemotherapy, sipuleucel-T, or investigational drug in prior 4 weeks, or abiraterone or enzalutamide in prior 2 week
More than 1 month of prior hormone exposure or hormone exposure within 30 days of registration; prior enzalutamide, ketoconazole, abiraterone, or TAK700 prohibited; prior 5alpha-reductase inhibitors are allowed
previously treated with abiraterone, enzalutamide alone or in combination AND must have demonstrated evidence of objective progression as per PCWG3 criteria
Treatment with abiraterone acetate for castration-resistant prostate cancer (CRPC) in the past is required; it does not need to be the last treatment prior to enrollment
Must have received at least 1 line of AR-targeted therapy or androgen bio-synthesis inhibitor (e.g., abiraterone acetate, enzalutamide, apalutamide) for prostate cancer (PCa)
Prior treatment with CYP17 inhibitor (e.g. ketoconazole, abiraterone acetate, galeterone) or second generation androgen receptor antagonist including apalutamide or enzalutamide
Prior treatment with abiraterone or other known potent CYP17 inhibitors (e.g., ketoconazole, orteronel) or investigational agents that block androgen synthesis. Previous treatment with itraconazole and fluconazole is permitted.
Prior abiraterone and enzalutamide are permitted, but not required
Patient’s physician has already recommended enzalutamide for treatment of progression
Patients must have received treatment with prior enzalutamide for greater than three 28-day cycles and must have had evidence of disease progression while on enzalutamide.
Prior treatments with TAK-700/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 PCWG3 criteria) and a castrate serum testosterone level (i.e. =< 50 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-17 inhibitors (e.g. ketoconazole, abiraterone)\r\n* Antiandrogens (e.g. bicalutamide, nilutamide)\r\n* Second generation antiandrogens (e.g. enzalutamide, ARN-509, Galeterone)\r\n* Immunotherapy (e.g. sipuleucel-T, ipilimumab)\r\n* Chemotherapy (e.g. docetaxel, cabazitaxel)
Cohort A: Patients must have progressed during treatment with abiraterone
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 160 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 28 days prior to the first dose of enzalutamide and/or CORT125281
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken. (Note: apalutamide does not have to be taken on an empty stomach)
Prior exposure to ketoconazole (systemic), abiraterone acetate, enzalutamide or other agents targeting the androgen receptor (AR) signaling pathway
Subject has been on abiraterone for castration-sensitive prostate cancer (CSPC) or castration-resistant prostate cancer (CRPC). Subjects who have received abiraterone for CSPC must have had a response to hormonal therapy, as defined by any decline in PSA, radiographic response and/or clinical benefit after starting hormonal therapy. Subjects who have received abiraterone for CRPC must have responded to abiraterone, defined by any decline in PSA, radiographic response, and/or clinical benefit after starting abiraterone.
Prior treatment with: LHRH agonist/antagonists; second generation androgen receptor (AR) inhibitors such as enzalutamide, ARN-509, darolutamide (ODM-201); other investigational AR inhibitors; CYP17 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
Prior treatment for prostate cancer, including ADT, orchiectomy, antiandrogens, ketoconazole, abiraterone acetate or enzalutamide
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken.
Previous use of abiraterone acetate or other investigational CYP17 inhibitor (e.g., TAK-700).
Have received prior abiraterone and/or enzalutamide
DISEASE SPECIFIC EXPANSION COHORTS: Prostate cancers patients enrolled on this study must have:\r\n* Metastatic or advanced (incurable and unresectable) castration resistant metastatic cancer\r\n* Received at least one additional line of anti-androgen therapy with abiraterone or enzalutamide\r\n* Measurable disease is not required for enrollment
Prior use of abiraterone and other hormonal agents used to treat prostate cancer are permitted but abiraterone acetate should be stopped prior to study treatment initiation
Documented disease progression (either radiographic or biochemical) on at least 1 novel hormonal therapy (enzalutamide and/or abiraterone acetate/prednisone) for the treatment of metastatic CRPC, irrespective of prior NHT treatment for non castrate prostate cancer or nonmetastatic (M0) CRPC.
No prior therapy with AR antagonists including but not limited to bicalutamide, enzalutamide, abiraterone and orteronel.
Patients enrolling in this trail should have received either Enzalutamide or Abiraterone
Subjects must have received, were ineligible to receive, or refused at least one cytotoxic chemotherapy and enzalutamide or abiraterone or both enzalutamide and abiraterone
Antiandrogens (e.g., bicalutamide, flutamide, nilutamide, abiraterone, enzalutamide) for > 2 months prior to consenting; patients on 5-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-509)
For subjects in Groups B or C, previous use of at least one androgen pathway inhibitor (either abiraterone acetate or enzalutamide) for metastatic CRPC
A minimum of 2 weeks off of enzalutamide or abiraterone, if applicable, prior to registration
Prior treatment with an anti-androgen (abiraterone, apalutamide [ARN-509], bicalutamide, enzalutamide, AR antagonist ODM-201 [ODM-201], TAK-448, TAK-683, orteronel [TAK-700], seviteronel [VT-464])
Prior treatment with an anti-androgen (abiraterone, ARN-509, bicalutamide, enzalutamide, ODM-201, TAK-448, TAK-683, TAK-700, VT-464)
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
Willing to take abiraterone acetate on an empty stomach (no food should be consumed at least two hours before and for one hour after dosing)
Prior use of apalutamide, abiraterone acetate or degarelix
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.
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 P450 (CYP)-17 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)
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 80 mg once daily
Prior therapy with abiraterone, enzalutamide and/or docetaxel; there is no limit to the number of prior treatment regimens
Prior treatment with abiraterone or enzalutamide is permitted, but patients must have been off prior corticosteroid treatment for at least 3 months
Prior treatment with anti-androgens other than enzalutamide is acceptable
Prior treatment with enzalutamide
Have metastatic castration-resistant prostate cancer, are chemo-naïve for mCRPC (however, six cycles of docetaxel are allowed in hormone-sensitive disease), and have progressed on abiraterone treatment (patients may have had prior therapy including sipuleucel-T, radium-223, abiraterone, ketoconazole, and/or Tak-700); progression on abiraterone is defined as\r\n* Radiologic progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Prostate Cancer Working Group (PCWG)2 criteria, or \r\n* PSA progression on abiraterone:\r\n** For responders to abiraterone: 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir, confirmed by a second value obtained 2 or more weeks later\r\n** For non-responders to abiraterone: 25% increase above baseline with an increase in absolute value of 2 ng/mL or more after 12 weeks of treatment
Must have had prior abiraterone treatment
Have had second-line hormonal therapy (abiraterone, ketoconazole, and/or Tak-700, etc.) within two weeks prior to the first dose of study drug; patients require a two-week wash out; patients may continue standard supportive dosing of prednisone and hydrocortisone for abiraterone and ketoconazole, respectively, as needed
Have had prior enzalutamide, ARN-509, 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, 2nd generation anti-androgen therapy (i.e. enzalutamide, abiraterone, etc.), or chemotherapy given as part of the treatment of prostate cancer
Greater than 2 prior therapies in metastatic CRPC (including single-agent docetaxel, abiraterone); abiraterone can only be taken pre-chemotherapy
For Cohorts A and B, patients must have progressed on prior treatment with enzalutamide or abiraterone acetate + prednisone (by PSA criteria or radiographically)
For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): prior treatment with up to 2 additional second line hormone therapies, including ketoconazole is allowed
For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): patients who have progressed on both enzalutamide and abiraterone acetate are eligible and post-BAT will be retreated with the last second line agent they had received (e.g. patient receiving abiraterone acetate [abiraterone] then enzalutamide would receive retreatment with enzalutamide post-BAT)
For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): patients must be withdrawn from enzalutamide or abiraterone acetate for >= 4 weeks and have documented PSA increase after the withdrawal period
For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): patients receiving prednisone in conjunction with abiraterone acetate must be weaned off prednisone prior to starting BAT
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-509 or other investigational androgen ablative therapies is permitted for Cohort C
Prior treatment with abiraterone acetate, enzalutamide, apalutamide (ARN-509), galeterone (TOK-001), orteronel (TAK-700), or similar agent
Subjects must have progressed on prior new hormonal agent (e.g. abiraterone acetate and/or enzalutamide) for the treatment of mCRPC.
Must have previously received at least 1, but no more than 2, 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 4 weeks of AR-targeted therapy
mCRPC that has progressed on at least 1 therapy progression (defined as Prostate Cancer Working Group 2 [PCWG2] or at investigators’ discretion) approved for treatment of mCRPC, one of which must include abiraterone acetate and/or enzalutamide
Any approved or investigational agent that blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, ARN-509, bicalutamide, enzalutamide, ODM-201, TAK-448, TAK-683, TAK-700)
Patients must have progressed on abiraterone and/or enzalutamide; there must be at least a 3-week washout period after stopping the most recent approved therapy for mCRPC (i.e., abiraterone, enzalutamide, Ra-223, sipuleucel-t); if applicable, patients should be weaned off steroids at least 1 week prior to starting treatment
Prior therapy with sipuleucel-T, abiraterone, enzalutamide, docetaxel, and/or cabazitaxel; there is no limit to the number of prior treatment regimens, so long as prior therapy does not include platinum chemotherapy or a PARP inhibitor
No prior abiraterone acetate, enzalutamide or apalutamide or other novel AR or CYP17 antagonist, or docetaxel for castration resistant prostate cancer; if used for hormone naïve disease, last dose was at least 12 months prior to randomization
Prior treatment with ARN-509 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 15 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 2 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 5 doses prior to enrollment in the trial are still considered eligible and not subject to wash-out
Expression of AR-V7 is not required as expression of AR-V7 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
Subjects must have failed prior therapy with abiraterone, enzalutamide, or both: has completed at least 12 weeks of prior continuous therapy with abiraterone or enzalutamide; has not been without abiraterone or enzalutamide treatment for >30 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 >7 days prior to dosing start with GSK525762 plus enzalutamide on trial, then a enzalutamide only lead-in dosing of 28 days is required
If the subject has enzalutamide discontinuation for <=7 days prior to dosing start with GSK525762 plus enzalutamide on trial, then a enzalutamide only lead-in dosing of 14 days is required
If the subject is on continuous dosing with enzalutamide prior to dosing start with GSK525762 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 3 days prior to dosing start with GSK525762 plus abiraterone on trial, then abiraterone only lead-in dosing of 7 days is required.
Recent prior therapy, defined as: Any investigational or approved non-biologic anti-cancer drug (see exception below) within 14 days prior to the first dose of GSK525762 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 42 days prior to the first dose of GSK525762 and abiraterone/enzalutamide, any anti-cancer biologic agents within five half-lives prior to the first dose of GSK525762 and abiraterone/enzalutamide, if the subject received radiotherapy <90 days prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response. Exception: Any radiotherapy within 14 days prior to the first dose of GSK525762 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 28 days prior to the first dose of GSK525762 and abiraterone/enzalutamide
Treatment with abiraterone within 2 weeks prior to study treatment
Prior use of enzalutamide
Prior treatment with other second line hormone therapy is allowed (e.g. flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, ARN-509); patients must be off these therapies for at least 4 weeks prior to starting treatment
Patients must not have received prior and/or must not have any plans for receiving concomitant therapy with ketoconazole, aminoglutethimide, or abiraterone acetate, or enzalutamide (MDV3100); concurrent megestrol for hot flashes is allowed
Disease progression according to Prostate Cancer Working Group 2 (PCWG2) criteria during or following treatment with an androgen pathway inhibitor (that is, enzalutamide, abiraterone) for metastatic CRPC
Treatment with approved anti-cancer therapy (with the exception of abiraterone) within 3 weeks of study drug. Abiraterone must not be administered within 2 weeks prior to initiation of study treatment
Subjects must have received abiraterone and/or enzalutamide. Subject must have received either abiraterone or enzalutamide for ?12 weeks. Other second generation CYP17 inhibitors/androgen receptor antagonists including but not limited to TAK-700 (orteronel), TOK-001 (galeterone) may have been taken in place of abiraterone and ARN-509 (apalutamide) may have been taken in place of enzalutamide.
For Cohort A: Has received docetaxel for mCRPC. Prior treatment with 1 other chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations (e.g., abiraterone acetate and/or enzalutamide) are allowed
For Cohort B: Has received prior treatment with either abiraterone acetate or enzalutamide (but not both) in the prechemotherapy mCRPC state. Participants in Cohort B must have received at least 4 weeks of either abiraterone or enzalutamide treatment (but not both) who failed treatment or became intolerant of the drug
For Cohort C: Has received prior treatment with abiraterone acetate in the pre-chemotherapy mCRPC state without prior enzalutamide. Participants in Cohort C must have received at least 4 weeks of abiraterone treatment who failed treatment or become intolerant of the drug.
Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, or enzalutamide for prostate cancer;
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-700, ARN-509, ODM-201).
Able to swallow a whole tablet and take abiraterone acetate on an empty stomach (defined as no food for two hours before and one hour after abiraterone acetate ingestion)
Patients must have progressed on abiraterone and/or enzalutamide.
For inclusion in Cohort 2, mCRPC patients must have progressed while receiving (or subsequent to receiving) abiraterone and/or enzalutamide and must have progressed subsequent to receiving ? 2 cycles of a taxane-based regimen for mCRPC.
Prior concomitant therapy with ketoconazole, aminoglutethimide or abiraterone acetate or enzalutamide (MDV3100) or intent to treat with the above. Concurrent megestrol for hot flashes is allowed.
Be eligible for treatment with physician's choice of comparator treatment (abiraterone acetate, enzalutamide or docetaxel)
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-509 or other investigational AR signaling inhibitors). The exception of spironolactone is allowed after Medical Monitor consultation.
Prior enzalutamide, abiraterone acetate, aminoglutethimide, ketoconazole, radium Ra 223 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
Concomitant use of medications that may alter pharmacokinetics of abiraterone (abiraterone acetate) or 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 6 week withdrawal period from the last dose of bicalutamide, or nilutamide or 4 weeks from last flutamide or enzalutamide dose\r\n** Must have a documented PSA rise after stopping the antiandrogen\r\n* Will require a 2 week washout period from last dose of ketoconazole, chemotherapy, radiation (including radium-223), or prior investigational systemic agents
Prior treatment with enzalutamide
Dose-escalation: prior treatment with abiraterone acetate; at least 4 weeks must have elapsed from the last dose of abiraterone acetate
Expansion cohort only (if conducted in the study): men with mCRPC and disease progression as defined by PCWG2 within 6 months (primary resistance); or after at least 6 months of treatment (acquired resistance) of starting treatment with abiraterone acetate; at least 4 weeks must have elapsed from the last dose of abiraterone acetate
Patients must have received treatment with either enzalutamide and/or abiraterone prior to study entry
Previous 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 targets the androgen receptor (e.g., enzalutamide, BMS 641988); ketoconazole
COHORT A: Prior ketoconazole, abiraterone acetate, or enzalutamide for the treatment of prostate cancer
Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone, or enzalutamide for the treatment of prostate cancer
Subject with a history of exposure to enzalutamide.
Previous exposure to any 2nd generation anti-hormonal including abiraterone and enzalutamide
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken
No prior enzalutamide, abiraterone, or other novel antiandrogen or androgen synthesis inhibitor
Prior treatment with enzalutamide
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken, and should be able to swallow tablets whole, without crushing/chewing tablets
Prior treatment with abiraterone acetate or enzalutamide
Prior use of abiraterone acetate or cytotoxic chemotherapy for prostate cancer
Prior treatment with enzalutamide, TOK-001, or ARN-509; 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
Patients who have been treated with abiraterone will be excluded
Prior history of CYP17 inhibitors (e.g., abiraterone acetate, TAK-700) and second-generation anti-androgen (e.g., MDV3100)
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken
Prior ketoconazole, abiraterone acetate, or enzalutamide for the treatment of prostate cancer
Prior treatment with CYP17 inhibitors or AR antagonists (e.g. abiraterone, TAK-700, ARN-509, ketoconazole*, enzalutamide, or galeterone) - Treatment naïve only
Prior treatment with CYP17 inhibitors (e.g. TAK-700, ketoconazole*) or AR antagonists (e.g. enzalutamide, ARN-509,) or galeterone - abiraterone refractory only
Prior treatment with CYP17 inhibitors (e.g. abiraterone, TAK-700, ketoconazole*) or AR antagonists (e.g. ARN -509) or galeterone - enzalutamide refractory only
Patients enrolled on the randomized portion of the study must have had disease progression on abiraterone or enzalutamide
Currently participating in an abiraterone acetate clinical study considered complete and had received at least 3 months of treatment with abiraterone acetate tablets.
Has taken commercially available enzalutamide (Xtandi);
Prior treatment with abiraterone
Must have received enzalutamide or apalutamide. (Note: additional therapies approved for CRPC prior to enzalutamide or apalutamide are allowed.) (Part 2 only)
Patients with rapidly progressive disease who are candidates for other approved therapies such as docetaxel, abiraterone, and enzalutamide.
Prior treatment with any anti-androgens, including but not limited to, enzalutamide and bicalutamide
Megesterol acetate
Demonstrated progression on abiraterone and/or enzalutamide
Received more than one treatment course of enzalutamide or abiraterone
Prior treatment with abiraterone acetate
Subject has been previously treated with enzalutamide for at least 8 months, and stopped enzalutamide due to progressive disease (not due to adverse events), followed by at least 4 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-223, 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.
Use of any antineoplastic treatment post-chemotherapy, including but not limited to aminoglutethimide, ketoconozole, abiraterone acetate, Rad-223, sipuleucel-T, or enzalutamide. Continuing steroids is permitted.
Treatment with abiraterone acetate prior to enzalutamide for metastatic castration - resistant prostate cancer (mCRPC) in the prechemotherapy setting. (Note: Patients who have received concomitant enzalutamide and abiraterone acetate therapies are not excluded).
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 (2 week washout for both agents)
CRPC subjects: Must have measurable disease by either: RECIST1.1 or a minimum PSA of 5 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 abiraterone treatment completed at least 4 weeks prior to cycle 1 day 1. Participants must have failed prior abiraterone treatment.
Prior treatment with enzalutamide.
PHASE II – GROUP B: Progressive disease must have occurred on abiraterone within the prior 12 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-17 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 28 days prior to receipt of enzalutamide, abiraterone, prednisone or denosumab
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 P450, family 17 (CYP-17) inhibitors (e.g. ketoconazole, abiraterone)\r\n* Antiandrogens (e.g. bicalutamide, nilutamide)\r\n* Second generation antiandrogens (e.g. ARN-509)\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-223, strontium-89, samarium-153)
Progressive disease (PD) while receiving AR targeted therapy with abiraterone acetate or enzalutamide within 12 months of treatment initiation (?12 months) by at least one of the following:
Prior AR targeted therapy (abiraterone acetate or enzalutamide) must be stopped at least 2 weeks before study treatment.
Known history of mineralocorticoid excess or deficiency (not applicable to patients who have already been treated with abiraterone acetate in first line before inclusion).
Abiraterone acetate; primary resistance to abiraterone will be defined as:\r\n* No PSA decline\r\n* PSA decline less than 50% after 12 weeks of abiraterone therapy\r\n* PSA progression within 12 weeks of abiraterone acetate (AA) treatment (by Prostate Cancer Working Group-2 [PCWG2] criteria), after initial response to therapy\r\n* Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting abiraterone treatment\r\n* Unequivocal clinical progression (per the treating provider's discretion) within 12 weeks of starting abiraterone treatment
Enzalutamide; primary resistance to enzalutamide will be defined as:\r\n* No PSA decline\r\n* PSA decline less than 50% after 12 weeks of enzalutamide therapy\r\n* PSA progression within 12 weeks of enzalutamide treatment (by PCWG2 criteria), after initial response to therapy\r\n* Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting enzalutamide treatment\r\n* Unequivocal clinical progression (per the treating provider's discretion) within 12 weeks of starting enzalutamide treatment
Combination therapy with abiraterone, enzalutamide and/or other second- generation investigational anti-androgen/androgen-receptor targeted therapies, including ARN-509; primary resistance to combination therapy will be defined as:\r\n* No PSA decline\r\n* PSA decline less than 50% after 12 weeks of abiraterone and enzalutamide therapy\r\n* PSA progression within 12 weeks of abiraterone and enzalutamide treatment (by PCWG2 criteria), after initial response to therapy\r\n* Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting abiraterone and enzalutamide treatment\r\n* Unequivocal clinical progression (per the treating provider’s discretion) within 12 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-509\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 28 days for the following therapies is required: abiraterone, enzalutamide, fluconazole, itraconazole, flutamide, bicalutamide, nilutamide, and other experimental hormonal agents (ARN509, orteronel [TAK-700], etc.), sipuleucel-T (Provenge), other experimental vaccines (PROSTVAC-V/F, etc.), strontium-89, samarium, and radium-223 chloride
Received prior abiraterone acetate, but not within the 3 months prior to study drug dosing
Willing to take abiraterone acetate on empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken
Treatment with at least 2 months of abiraterone prior to progression
Prior therapy with abiraterone, or aminoglutethimide
Prior use of ketoconazole, abiraterone acetate or enzalutamide, or participation in a previous clinical trial of ketoconazole, abiraterone acetate or enzalutamide
Completed at least 12 weeks of prior continuous therapy with enzalutamide. A 2 week or less treatment (enzalutamide) holiday will be permitted prior to initiating study treatment.
Prior use of or participation in a clinical trial evaluating and agent that either blocks androgen synthesis (e.g. abiraterone acetate, TAK-700, TAK-683, TAK-44) or targets the AR (e.g., bicalutamide, BMS-641988) (patients who are known to have only received placebo in these studies are eligible)
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken
Patients may have received secondary hormonal manipulations (excluding prior abiraterone acetate, MDV3100 or TAK700) or up to two lines of chemotherapy; all prior therapy except Lupron must have been discontinued for more than 4 weeks before enrollment
Patients must have received at least one of the approved products known to improve the overall survival of patients with metastatic castration resistant prostate cancer (i.e. abiraterone, enzalutamide, sipuleucel-t, radium-223, docetaxel or cabazitaxel)
Investigational therapy other than enzalutamide.
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and or at least one hour after the dose abiraterone acetate is taken
Additional ADT agents may be concurrently administered (abiraterone, bicalutamide, enzalutamide, etc.)
Dose Escalation only: Enzalutamide-naïve patients following prior progression on abiraterone by PCWG2 criteria and within 12 weeks of discontinuing abiraterone
Dose Confirmation Cohort B (DC-B) only: Enzalutamide-naïve patients following prior progression on abiraterone by PCWG2 criteria and within 12 weeks of discontinuing abiraterone
Initiated therapy with either abiraterone plus a glucocorticoid or enzalutamide within the 3 months prior to randomization
No prior exposure to abiraterone acetate or other specific CYP-17 inhibitors
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-509) or another systemic therapy for mCRPC
Patients starting abiraterone or starting enzalutamide ), within approximately 1-7 days of baseline 18F-DCFPyL PET/CT
Failed prior therapy with a secondary hormone (e.g. enzalutamide, abiraterone) with documented progressive disease (post-secondary hormone CRPC)
For pre-secondary hormone patients, no prior or concurrent treatment with a secondary hormone (e.g. enzalutamide, abiraterone)
For post-secondary hormone patients, no concurrent treatment with a secondary hormone (e.g. enzalutamide, abiraterone), no metastasis to the liver or brain
Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g., *6) will be allowed and treated as in the *28/*28 dosing group
Homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) or heterozygotes for UGT1A1*28 (UGT1A11 7/6 genotype) only for the phase I part
Concurrent use of any medication that is an inhibitor of UGT1A9 during the screening or treatment period
UGT1A1*28 homozygote or heterozygote
Subjects who are homozygous for the UGT1A1*28 allele
Use of UDP glucuronosyltransferase 1 family, polypeptide A9 (UGT1A9) inhibitor including: diclofenac, imipramine, and ketoconazole
Use of any UGT1A9 inhibitor from screening through follow-up period, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid
Use of any UGT1A9 inhibitor from screening through follow-up period, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid
Use of any UGT1A9 inhibitor while on active study treatment, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid
Subjects with UGT1A1*28 polymorphisms.
Concomitant use of a UGT1A1 inhibitor, such as idinavir, atazanavir and sorafenib, throughout the study period.
Patients who require treatment with UGT1A1 inhibitors during the period of investigational treatment with DFP-13318.
Patients with known Gilbert's syndrome or reduced UGT1A1 activity.
Uridine diphosphate (UDP) glycosyltransferase 1 family, polypeptide A1 (UGT1A1) *28 homozygous patients
Use of drugs known to inhibit UGT1A1, such as atazanir, gemfibrozil, indinavir, or ketoconazole, within 2 weeks prior to start of study treatment
UGT1A1 genotyping prior to treatment
UGT1A1 genotype other than *1/*1, *1/*28, or *28/*28
Patients on a medication or herbal therapy known to inhibit cytochrome P450 (CYP)2A6, UGT1A9, or UGT2B7
DOSE ESCALATION COHORT: Use of any UGT1A9 inhibitor from screening through follow-up period, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid
DOSE EXPANSION COHORT: Use of any UGT1A9 inhibitor from screening through follow-up period, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid
Use of any uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A9 (UGT1A9) inhibitor including: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid from screening through follow-up period
Use of any UDP glucuronosyltransferase 1 family, polypeptide A9 (UGT1A9) inhibitor including: acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, imipramine, ketoconazole, linoleic acid, mefenamic acid, mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, phenytoin, and probenecid propofol, quinidine, ritonavir, sorafenib, sulfinpyrazone, valproic acid, and verapamil; patients must avoid UGT1A9 inhibitors from the screening period through active treatment with INCB024360 and for one week after discontinuation of INCB024360
Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g., *6)
Patients must not have a known history of Gilbert’s syndrome or known homozygosity for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele
Evidence of Gilbert’s syndrome or known homozygosity for the UGT1A1*28 allele (special screening not required)
A history of known Gilbert’s syndrome or homozygous presence of the uridine diphosphate (UDP)-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele on pre-treatment testing
Patients who are already known homozygous for the UDP glycosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele, and patients of Asian descent homozygous or heterozygous for the UGT1A1*6 allele will be excluded
Total bilirubin =< 2 x ULN (except for patients with uridine diphosphate glucuronosyltransferase 1A1 [UGT1A1] promoter polymorphism, i.e. Gilbert syndrome, confirmed by genotyping or invader UGT1A1 molecular assay prior to study enrollment; patients enrolled with Gilbert syndrome must have total bilirubin < 3 ULN)
Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g, *6)
Use of drugs known to inhibit UDP glycosyltransferase 1 family, polypeptide A1 gene (UGT1A1), such as Atazanavir, Gemfibrozil, Indinavir, or Ketoconazole while on study treatment; (patients using these drugs must not take these drugs on the day study treatment begins and for the duration of study treatment)
Any known UGT1A polymorphism, heterozygous or homozygous
UGT1A1 genotype of TA 7 in both alleles (homozygous UGT1A1*28) or TA 8 in either one or both alleles (hetero- or homozygous for UGT1A1*37)
UGT1A1 genotype of TA 7 in both alleles (homozygous UGT1A1*28) or TA 8 in either one or both alleles (hetero- or homozygous for UGT1A1*37)
Homozygous UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 (i.e. 7 TA repeats) gene alleles; the UGT1A1 test should be conducted per local institutional practice
Patients genotyped for UGT1A1*28 polymorphism with *1/*1 or *1/*28 genotype
Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g, *6)
Patients with Gilbert’s syndrome unless homozygosity for the uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 mutation has been excluded
Known homozygous for UGT1A1*28 mutation from prior testing or family history
Requirement of therapy with a UGT1A1 Inhibitor, or use within 7 days of enrollment on this protocol