A Study of Apalutamide (JNJ-56021927, ARN-509) Plus Androgen Deprivation Therapy (ADT) Versus ADT in Participants With mHSPC (TITAN)

• ClinicalTrials.gov Identifier: NCT02489318
• Recruitment Status: Active, not recruiting
• First Posted: July 3, 2015
• Results First Posted: January 18, 2022
• Last Update Posted: April 25, 2024
• Sponsor: Aragon Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Aragon Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: July 1, 2015
• First Posted Date: July 3, 2015
• Results First Submitted Date: September 6, 2021
• Results First Posted Date: January 18, 2022
• Last Update Posted Date: April 25, 2024
• Actual Study Start Date: November 27, 2015
• Actual Primary Completion Date: September 7, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 17, 2021)

• Radiographic Progression-free Survival (rPFS) [ Time Frame: Up to 35 months ]
  rPFS as assessed by the investigator was defined as the duration from the date of randomization to the date of first documentation of radiographic progressive disease or death due to any cause, whichever occurred first. Radiographic progressive disease was defined as progression of soft tissue lesions measured by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by modified Response evaluation criteria in solid tumors (RECIST) 1.1.
• Overall Survival (OS) [ Time Frame: Up to 57 months ]
  OS was defined as the time from date of randomization to date of death from any cause.

Original Primary Outcome Measures (submitted: July 1, 2015)

• Radiographic Progression-Free Survival (rPFS) [ Time Frame: Up to 76 Months ]
  The rPFS is defined as the duration from the date of randomization to the date of first documentation of radiographic progressive disease or death due to any cause, whichever occurs first.
• Overall Survival (OS) [ Time Frame: Up to 76 Months ]
  The OS is defined as the time from date of randomization to date of death from any cause.

Current Secondary Outcome Measures (submitted: December 17, 2021)

• Time to Initiation of Cytotoxic Chemotherapy [ Time Frame: Up to 57 months ]
  Time to initiation of cytotoxic chemotherapy was defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.
• Time to Pain Progression [ Time Frame: Up to 57 months ]
  Time to pain progression was defined as the time from the date of randomization to the date of the first observation of pain progression. Pain progression was defined as an average increase by 2 points from baseline to greater than (>) 4 on the Brief Pain Inventory - Short Form (BPI-SF) worst pain intensity (item 3) with no decrease in opioids confirmed greater than equal to (>=) 3 weeks apart or initiation of chronic opioids, whichever occurred first. BPI-SF is a self-administered questionnaire developed to assess severity of pain and impact of pain on daily functions. Item 3 (worst pain intensity) asks participants to rate worst pain in prior 7-days on a 0-10 numeric rating scale, where "0" indicates "No pain" and "10" indicates "Pain as bad as you can imagine." A lower score is better.
• Time to Chronic Opioid Use [ Time Frame: Up to 57 months ]
  Time to chronic opioid use was defined as the time from date of randomization to the first date of confirmed chronic opioid use. For participants entering the study without receiving opioids, chronic opioid use was defined as administration of opioid analgesics lasting for greater than or equal to (>=) 3 weeks for oral or >=7 days for non-oral formulations. For participants entering the study already receiving opioids, chronic opioid use was defined as a >=30 percent (%) increase in total daily dose of the opioid analgesics lasting for >= 3 weeks for oral or >= 7 days for non-oral formulation.
• Time to Skeletal-related Event (SRE) [ Time Frame: Up to 57 months ]
  Time to SRE was defined as the time from the date of randomization to the date of the first observation of an SRE. A SRE was defined as the occurrence of either a pathological fracture, or spinal cord compression, or radiation to bone, or surgery to bone.

Original Secondary Outcome Measures (submitted: July 1, 2015)

• Time to Pain Progression [ Time Frame: Up to 76 Months ]
  Time to pain progression is defined as the time from the date of randomization to the date of the first observation of pain progression.
• Time to Skeletal-Related Event (SRE) [ Time Frame: Up to 76 Months ]
  Time to SRE is defined as the time from the date of randomization to the date of the first occurrence of a fracture or treatment for the fracture. The SRE is defined as the occurrence of either pathological or clinical fracture, spinal cord compression, radiation to bone, or surgery to bone.
• Time to Chronic Opioid Use [ Time Frame: Up to 76 Months ]
  Time to chronic opioid use is defined as the time from date of randomization to the first date of opioid use or first date of an increase in the total daily dose.
• Time to Initiation of Cytotoxic Chemotherapy [ Time Frame: Up to 76 Months ]
  Time to initiation of cytotoxic chemotherapy is defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Apalutamide (JNJ-56021927, ARN-509) Plus Androgen Deprivation Therapy (ADT) Versus ADT in Participants With mHSPC
• Official Title: A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Apalutamide Plus Androgen Deprivation Therapy (ADT) Versus ADT in Subjects With Metastatic Hormone-sensitive Prostate Cancer (mHSPC)
• Brief Summary: The purpose of this study is to determine if the addition of apalutamide to ADT provides superior efficacy in improving radiographic progression-free survival (rPFS) or overall survival (OS) for participants with mHSPC.
• Detailed Description: This is a randomized (study medication assigned to participants by chance), double-blind (neither the researchers nor the participants know what treatment the participant is receiving), placebo-controlled, multinational, multicenter study of apalutamide in participants with mHSPC. The study consists of 4 Phases: Screening Phase (up to 28 days before randomization), Treatment Phase (28 day treatment cycles until disease progression or the occurrence of unacceptable treatment related toxicity), an End of Treatment Phase (until 30 days after the last dose of study drug), and then a Survival Follow up Phase. In the event of a positive study result and notification of unblinding at either of the interim analyses or at the final analysis, participants in the treatment Phase will have the opportunity to enroll in an Open-label Extension Phase, which will allow participants to receive active drug (apalutamide) for approximately 3 years. Participants who are receiving apalutamide in the Open-label Extension Phase may continue receiving apalutamide in the Long-term Extension (LTE) Phase if they will continue to derive benefit from treatment (based on investigator assessment). Participants' safety will be monitored throughout the study.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

• Drug: Apalutamide
  Participants will receive apalutamide 240 mg (4 x 60 mg) tablets orally once daily in each 28 day treatment cycles.
  Other Names:

  • JNJ-56021927
  • ARN-509
• Drug: Placebo
  Participants will receive Placebo orally once daily in each 28 day treatment cycles.
• Drug: Androgen Deprivation Therapy (ADT)
  All participants will receive and remain on a stable regimen of ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration). The choice of the GnRHa (agonist or antagonist) will be at discretion of the Investigator. Dosing (dose and frequency of administration) will be consistent with the prescribing information.

Study Arms

• Experimental: Apalutamide plus ADT
  Participants will receive apalutamide 240 milligram (mg) (4X 60 mg tablets) with ADT.
  Interventions:

  • Drug: Apalutamide
  • Drug: Androgen Deprivation Therapy (ADT)
• Experimental: Placebo plus ADT
  Participants will receive matching Placebo with ADT.
  Interventions:

  • Drug: Placebo
  • Drug: Androgen Deprivation Therapy (ADT)

Publications *

• Agarwal N, McQuarrie K, Bjartell A, Chowdhury S, Pereira de Santana Gomes AJ, Chung BH, Ozguroglu M, Juarez Soto A, Merseburger AS, Uemura H, Ye D, Given R, Basch E, Miladinovic B, Lopez-Gitlitz A, Chi KN. Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study. J Urol. 2021 Oct;206(4):914-923. doi: 10.1097/JU.0000000000001841. Epub 2021 May 27.
• Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juarez A, Merseburger AS, Ozguroglu M, Uemura H, Ye D, Brookman-May S, Mundle SD, McCarthy SA, Larsen JS, Sun W, Bevans KB, Zhang K, Bandyopadhyay N, Agarwal N. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021 Jul 10;39(20):2294-2303. doi: 10.1200/JCO.20.03488. Epub 2021 Apr 29.
• Uemura H, Koroki Y, Iwaki Y, Imanaka K, Kambara T, Lopez-Gitlitz A, Smith A, Uemura H. Skin rash following Administration of Apalutamide in Japanese patients with Advanced Prostate Cancer: an integrated analysis of the phase 3 SPARTAN and TITAN studies and a phase 1 open-label study. BMC Urol. 2020 Sep 2;20(1):139. doi: 10.1186/s12894-020-00689-0. Erratum In: BMC Urol. 2020 Oct 22;20(1):166.
• Agarwal N, McQuarrie K, Bjartell A, Chowdhury S, Pereira de Santana Gomes AJ, Chung BH, Ozguroglu M, Juarez Soto A, Merseburger AS, Uemura H, Ye D, Given R, Cella D, Basch E, Miladinovic B, Dearden L, Deprince K, Naini V, Lopez-Gitlitz A, Chi KN; TITAN investigators. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2019 Nov;20(11):1518-1530. doi: 10.1016/S1470-2045(19)30620-5. Epub 2019 Sep 29.
• Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juarez Soto A, Merseburger AS, Ozguroglu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S; TITAN Investigators. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019 Jul 4;381(1):13-24. doi: 10.1056/NEJMoa1903307. Epub 2019 May 31.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 7, 2018): 1052
• Original Estimated Enrollment (submitted: July 1, 2015): 1000
• Estimated Study Completion Date: September 5, 2024
• Actual Primary Completion Date: September 7, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of prostate adenocarcinoma as confirmed by the investigator
• Metastatic disease documented by greater than or equal to (>=) 1 bone lesions on 99mTc bone scan. Participants with a single bone lesion must have confirmation of bone metastasis by computed tomography (CT) or magnetic resonance imaging (MRI)
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade of 0 or 1
• Participants who received docetaxel treatment must meet the following criteria: a) Received a maximum of 6 cycles of docetaxel therapy for mHSPC; b) Received the last dose of docetaxel <=2 months prior to randomization; c) Maintained a response to docetaxel of stable disease or better, by investigator assessment of imaging and PSA, prior to randomization
• Other allowed prior treatment for mHSPC: a) Maximum of 1 course of radiation or surgical intervention; radiation therapy for metastatic lesions must be completed prior to randomization; b) Less than or equal to (<=) 6 months of ADT prior to randomization
• Allowed prior treatments for localized prostate cancer (all treatments must have been completed >= 1 year prior to randomization) a) <= 3 years total of ADT; b) All other forms of prior therapies including radiation therapy, prostatectomy,lymph node dissection, and systemic therapies

Exclusion Criteria:

• Pathological finding consistent with small cell, ductal or neuroendocrine carcinoma of the prostate
• Known brain metastases
• Lymph nodes as only sites of metastases
• Visceral (ie, liver or lung) metastases as only sites of metastases
• Other prior malignancy less than or equal to 5 years prior to randomization with the exception of squamous or basal cell skin carcinoma or non-invasive superficial bladder cancer
• Prior treatment with other next generation anti-androgens or other CYP17 inhibitors, immunotherapy or radiopharmaceutical agents for prostate cancer
• History of seizures or medications known to lower seizure threshold

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, Canada, China, Czechia, France, Germany, Hungary, Israel, Japan, Korea, Republic of, Mexico, Poland, Romania, Russian Federation, Spain, Sweden, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02489318
• Other Study ID Numbers: CR107614; 2015-000735-32 ( EudraCT Number ); 56021927PCR3002 ( Other Identifier: Janssen Research & Development, LLC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Aragon Pharmaceuticals, Inc.
• Original Responsible Party: Janssen Research & Development, LLC
• Current Study Sponsor: Aragon Pharmaceuticals, Inc.
• Original Study Sponsor: Janssen Research & Development, LLC
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Aragon Pharmaceuticals, Inc.
• Verification Date: April 2024