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  string(2297) "Background: the oncological outcomes of mCRPC patients are still heterogeneous. The diverse responses of Androgen Receptor targeting agents (e.g., second-generation androgen receptor inhibitors or biosynthesis inhibitors) illustrate the urgent need to apply the understanding of prostate cancer biology to clinical decision-making. To overcome this unmet need, some authors introduced the concept of Androgen indifferent prostate cancer (AIPC) variants, an umbrella term including aggressive variant prostate cancer (AVPC), neuroendocrine prostate cancer (NEPC), and double negative prostate cancer (DNPC), based on clinical and pathological features. These clinical criteria have not been implemented in clinical trial inclusion criteria yet.
Objective: to explore whether these clinical criteria truly identify patients not responding to novel antiandrogen therapies (ARTAs) and their combinations
Study design: a pooled analysis of randomized clinical trials and prospective cohorts of mCRPC patients.
Participants: mCRPC patients
Primary and Secondary outcomes: progression-free survival (PFS) overall survival (OS) and cancer-specific survival (CSS) and other cause mortality (OCM) of mCRPC patients. To identify oncological outcomes of AIPC based on different treatment regimes (ARTA vs ARTAs combination vs Taxanes based chemotherapy vs ADT monotherapy).
Statistical analysis: based on the definition of AIPC, the whole population will be split into two groups. Multivariable cox regression analysis will test the association of AIPC status with oncological outcomes, namely PFS, and OS. The Gray test will be employed to test the equality of the cumulative incidence functions in the presence of competing events Moreover, for those patients defined as AIPC, a comparison of different treatment regimens will be performed using multivariate cox regression analysis. Similarly, we will rely on the competing risks method to display the cumulative incidence functions for CSS and other causes of mortality (OCM) rates for the two aforementioned groups. Finally, if the AIPC clinical criteria fail to identify poor responders to ARTAs and their combinations, an analysis of intermediate clinical endpoints (ICE) will be performed according to Prentice Criteria." ["project_brief_bg"]=> string(1915) "The recent development of novel antiandrogen therapies has challenged the perception that most men with prostate cancer benefit from androgen ablation uniformly. The diverse responses to these recently approved therapies with distinct mechanisms of action (e.g., second-generation androgen biosynthesis inhibitors) have exposed the biological heterogeneity of prostate cancer and illustrate the urgent need to apply our understanding of prostate cancer biology to clinical decision-making. To overcome this unmet need, some authors introduced the concept of Androgen indifferent prostate cancer (AIPC) variants, an umbrella term including aggressive variant prostate cancer (AVPC), neuroendocrine prostate cancer (NEPC), and double negative prostate cancer (DNPC). Often the clinical criteria defining these entities show some degree of overlapping, resulting in these phenotypes being ill-defined. Yet, these androgen-independent variants are associated with poor outcomes. Given the treatment intensification trend in PCA, they are becoming increasingly common clinically meaningful entities.
The investigators will explore whether AVPC clinical criteria, proposed by Aparicio et al., truly identify patients not responding to novel antiandrogen therapies (ARTAs) and their combinations, sparing patients from potential side effects related to their use, such as major cardiac events (MACES). Moreover, the oncological outcomes of AIPC patients receiving different chemo-hormonal regimens will be compared.
The results of our work may affect clinical trial inclusion criteria, sparing AIPC from receiving AR targeting agents. Moreover, if the AIPC clinical criteria fail to identify poor responders to ARTAs and their combinations, identifying the most informative intermediate clinical endpoint may expedite randomized clinical trial results by shortening the follow-up needed for study completion." ["project_specific_aims"]=> string(525) "The investigator seeks to analyze whether Androgen indifferent prostate cancer (AIPC) clinical criteria identify patients not responding to novel antiandrogen therapies (ARTAs), their combinations, and androgen deprivation therapy alone. Moreover, a comparison with other treatment regimens will be carried out. So far, no study has evaluated the best treatment regimen for these patients. If these criteria fail to identify poor responders, an analysis of intermediate clinical endpoints (ICEs) in mCRPC will be carried out." ["project_study_design"]=> array(2) { ["value"]=> string(5) "other" ["label"]=> string(5) "Other" } ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(4) { [0]=> array(2) { ["value"]=> string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations" ["label"]=> string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations" } [1]=> array(2) { ["value"]=> string(76) "Confirm or validate previously conducted research on treatment effectiveness" ["label"]=> string(76) "Confirm or validate previously conducted research on treatment effectiveness" } [2]=> array(2) { ["value"]=> string(28) "Research on comparison group" ["label"]=> string(28) "Research on comparison group" } [3]=> array(2) { ["value"]=> string(50) "Research on clinical prediction or risk prediction" ["label"]=> string(50) "Research on clinical prediction or risk prediction" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> array(2) { ["value"]=> string(86) "not_analyzing_participant_level_data__plan_to_use_another_secure_data_sharing_platform" ["label"]=> string(92) "I am not analyzing participant-level data / plan to use another secure data sharing platform" } ["project_software_used_exp"]=> string(73) "I am going to complete the statistical analysis using VIVLI.org platform." ["project_research_methods"]=> string(204) "INCLUSION CRITERIA:
- mCRCP patients
- age >18 yo
Pfizer and Sanofi studies will also be used:
NCT01254279
NCT01308580
NCT02485691
EXCLUSION CRITERIA
- none" ["project_main_outcome_measure"]=> string(196) "The specific outcomes are:
- Overall survival
- Disease-specific survival
- Progression free survival
- Other cause mortality rate
- Major Cardiac Adverse events rate" ["project_main_predictor_indep"]=> string(946) "The independent variable that will be investigated will be:
- Androgen indifferent prostate cancer (AIPC) status (yes vs no)
CRPC characterized by one or more of the following clinical, pathological, or radiological features, was defined as AIPC:
? histologic evidence of SCPC (pure or mixed);
? presence of only visceral metastases;
? predominantly lytic bone lesions;
? bulky (> or = 5 cm) lymphadenopathy or large (> or = 5 cm) high-grade (Gleason > or = 8) tumor mass in prostate/pelvis;
? low PSA at presentation with extensive bone metastatic disease;
? presence of NE markers at histology (Chromogranin A and synaptophysin) or serum (CgA and gastrin-releasing peptide) combined with either elevated lactate dehydrogenase (LDH), malignant hypercalcemia or elevated serum carcinoembryonic antigen (CEA);
? progression to CRPC in six months or less after initiation of hormonal therapy." ["project_other_variables_interest"]=> string(1078) "Age, ethnicity, type of prior treatment, M status at diagnosis (M0 vs M1a vs M1b vs M1c), metastatic sites, time from ADT to mCRPC status, serum PSA at diagnosis, serum PSA at the start of treatment, for M+ disease burden at diagnosis (low volume vs high volume), lytic bone metastasis (yes vs no), neuroendocrine biomarkers status (synaptophysin, chromogranin A, if available), bulky lymphadenopathy (>or = 5 cm) in the pelvis (yes vs no), bulky high-grade mass (> or = 5 cm, Gleason > or = 8) in the prostate (yes vs no), serum CEA and/or LDH concentrarion (if available), neuroendocrine prostate cancer histology (yes vs mixed vs no), concurrent treatment at the time of diagnosis, previous treatment for prostate cancer, ECOG performance status, treatment regimen (ARTA vs ARTAs combination vs Taxanes vs ADT alone), major cardiac events (MACEs) rate after mCRPC treatment initiation, time to major cardiac events, family history of prostate cancer (yes vs no) and the number of relatives, family history of other malignancy, p53, pRB, PTEN mutation status if available." ["project_stat_analysis_plan"]=> string(984) "The investigator seeks to analyze the impact of Androgen indifferent prostate cancer (AIPC) status on survival outcomes, namely overall survival and progression-free survival by means of the Cox regression or the Fine and Gray regression, if data on cancer specific mortality and other cause mortality is available, according to ARTAs-based treatment or chemotherapy regimens. Survival curves will be plotted according to the Kaplan-Meier method for overall survival and to the competing risks method for cancer specific mortality, if available. Moreover, intermediate clinical endpoints (ICEs) will be investigated, according to Prentice Criteria. Multivariable Cox regression analyses will be exploited to predict overall survival at different landmark points to evaluate the impact of the different intermediate endpoints.
Data on comorbidities, medical therapies at the time of randomization, survival and response outcomes will be necessary to carry out the proposed study." ["project_timeline"]=> string(9) "12 months" ["project_dissemination_plan"]=> string(118) "The study will be submitted to peer-reviewed journals for publication. Ideally on The Lancet Oncology or JAMA Oncology" ["project_bibliography"]=> string(115) "

Berchuck et al. Prostate Cancer Prostatic Dis. 2021 September.
Spetsieris et al Cancers 2020 Disease.

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2022-5106

General Information

How did you learn about the YODA Project?: Other

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT00638690 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Docetaxel-Based Chemotherapy
  2. NCT00887198 - A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer
  3. NCT01695135 - A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (JNJ-212082) Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Docetaxel-Based Chemotherapy
  4. NCT02236637 - A Prospective Registry of Patients With a Confirmed Diagnosis of Adenocarcinoma of the Prostate Presenting With Metastatic Castrate-Resistant Prostate Cancer
  5. NCT01795703 - A Phase II Study of JNJ-212082 (Abiraterone Acetate) in Metastatic Castration-Resistant Prostate Cancer Patients Who Have Received Docetaxel-based Chemotherapy
  6. NCT01867710 - A Randomized Phase 2 Study Evaluating Abiraterone Acetate With Different Steroid Regimens for Preventing Symptoms Associated With Mineralocorticoid Excess in Asymptomatic, Chemotherapy-naïve and Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients
  7. NCT01715285 - A Randomized, Double-blind, Comparative Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Subjects With High-Risk, Metastatic Hormone-naive Prostate Cancer (mHNPC)
  8. NCT01591122 - A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (JNJ-212082) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer
  9. NCT02257736 - A Phase 3 Randomized, Placebo-controlled Double-blind Study of JNJ-56021927 in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Subjects With Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer (mCRPC)
What type of data are you looking for?:

Request Clinical Trials

Data Request Status

Status: Ongoing

Research Proposal

Project Title: Assessing the Androgen indifferent prostate cancer patients response to novel antiandrogen-based regimen or taxanes

Scientific Abstract: Background: the oncological outcomes of mCRPC patients are still heterogeneous. The diverse responses of Androgen Receptor targeting agents (e.g., second-generation androgen receptor inhibitors or biosynthesis inhibitors) illustrate the urgent need to apply the understanding of prostate cancer biology to clinical decision-making. To overcome this unmet need, some authors introduced the concept of Androgen indifferent prostate cancer (AIPC) variants, an umbrella term including aggressive variant prostate cancer (AVPC), neuroendocrine prostate cancer (NEPC), and double negative prostate cancer (DNPC), based on clinical and pathological features. These clinical criteria have not been implemented in clinical trial inclusion criteria yet.
Objective: to explore whether these clinical criteria truly identify patients not responding to novel antiandrogen therapies (ARTAs) and their combinations
Study design: a pooled analysis of randomized clinical trials and prospective cohorts of mCRPC patients.
Participants: mCRPC patients
Primary and Secondary outcomes: progression-free survival (PFS) overall survival (OS) and cancer-specific survival (CSS) and other cause mortality (OCM) of mCRPC patients. To identify oncological outcomes of AIPC based on different treatment regimes (ARTA vs ARTAs combination vs Taxanes based chemotherapy vs ADT monotherapy).
Statistical analysis: based on the definition of AIPC, the whole population will be split into two groups. Multivariable cox regression analysis will test the association of AIPC status with oncological outcomes, namely PFS, and OS. The Gray test will be employed to test the equality of the cumulative incidence functions in the presence of competing events Moreover, for those patients defined as AIPC, a comparison of different treatment regimens will be performed using multivariate cox regression analysis. Similarly, we will rely on the competing risks method to display the cumulative incidence functions for CSS and other causes of mortality (OCM) rates for the two aforementioned groups. Finally, if the AIPC clinical criteria fail to identify poor responders to ARTAs and their combinations, an analysis of intermediate clinical endpoints (ICE) will be performed according to Prentice Criteria.

Brief Project Background and Statement of Project Significance: The recent development of novel antiandrogen therapies has challenged the perception that most men with prostate cancer benefit from androgen ablation uniformly. The diverse responses to these recently approved therapies with distinct mechanisms of action (e.g., second-generation androgen biosynthesis inhibitors) have exposed the biological heterogeneity of prostate cancer and illustrate the urgent need to apply our understanding of prostate cancer biology to clinical decision-making. To overcome this unmet need, some authors introduced the concept of Androgen indifferent prostate cancer (AIPC) variants, an umbrella term including aggressive variant prostate cancer (AVPC), neuroendocrine prostate cancer (NEPC), and double negative prostate cancer (DNPC). Often the clinical criteria defining these entities show some degree of overlapping, resulting in these phenotypes being ill-defined. Yet, these androgen-independent variants are associated with poor outcomes. Given the treatment intensification trend in PCA, they are becoming increasingly common clinically meaningful entities.
The investigators will explore whether AVPC clinical criteria, proposed by Aparicio et al., truly identify patients not responding to novel antiandrogen therapies (ARTAs) and their combinations, sparing patients from potential side effects related to their use, such as major cardiac events (MACES). Moreover, the oncological outcomes of AIPC patients receiving different chemo-hormonal regimens will be compared.
The results of our work may affect clinical trial inclusion criteria, sparing AIPC from receiving AR targeting agents. Moreover, if the AIPC clinical criteria fail to identify poor responders to ARTAs and their combinations, identifying the most informative intermediate clinical endpoint may expedite randomized clinical trial results by shortening the follow-up needed for study completion.

Specific Aims of the Project: The investigator seeks to analyze whether Androgen indifferent prostate cancer (AIPC) clinical criteria identify patients not responding to novel antiandrogen therapies (ARTAs), their combinations, and androgen deprivation therapy alone. Moreover, a comparison with other treatment regimens will be carried out. So far, no study has evaluated the best treatment regimen for these patients. If these criteria fail to identify poor responders, an analysis of intermediate clinical endpoints (ICEs) in mCRPC will be carried out.

Study Design: Other

What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations Confirm or validate previously conducted research on treatment effectiveness Research on comparison group Research on clinical prediction or risk prediction

Software Used: I am not analyzing participant-level data / plan to use another secure data sharing platform

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: INCLUSION CRITERIA:
- mCRCP patients
- age >18 yo
Pfizer and Sanofi studies will also be used:
NCT01254279
NCT01308580
NCT02485691
EXCLUSION CRITERIA
- none

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: The specific outcomes are:
- Overall survival
- Disease-specific survival
- Progression free survival
- Other cause mortality rate
- Major Cardiac Adverse events rate

Main Predictor/Independent Variable and how it will be categorized/defined for your study: The independent variable that will be investigated will be:
- Androgen indifferent prostate cancer (AIPC) status (yes vs no)
CRPC characterized by one or more of the following clinical, pathological, or radiological features, was defined as AIPC:
? histologic evidence of SCPC (pure or mixed);
? presence of only visceral metastases;
? predominantly lytic bone lesions;
? bulky (> or = 5 cm) lymphadenopathy or large (> or = 5 cm) high-grade (Gleason > or = 8) tumor mass in prostate/pelvis;
? low PSA at presentation with extensive bone metastatic disease;
? presence of NE markers at histology (Chromogranin A and synaptophysin) or serum (CgA and gastrin-releasing peptide) combined with either elevated lactate dehydrogenase (LDH), malignant hypercalcemia or elevated serum carcinoembryonic antigen (CEA);
? progression to CRPC in six months or less after initiation of hormonal therapy.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Age, ethnicity, type of prior treatment, M status at diagnosis (M0 vs M1a vs M1b vs M1c), metastatic sites, time from ADT to mCRPC status, serum PSA at diagnosis, serum PSA at the start of treatment, for M+ disease burden at diagnosis (low volume vs high volume), lytic bone metastasis (yes vs no), neuroendocrine biomarkers status (synaptophysin, chromogranin A, if available), bulky lymphadenopathy (>or = 5 cm) in the pelvis (yes vs no), bulky high-grade mass (> or = 5 cm, Gleason > or = 8) in the prostate (yes vs no), serum CEA and/or LDH concentrarion (if available), neuroendocrine prostate cancer histology (yes vs mixed vs no), concurrent treatment at the time of diagnosis, previous treatment for prostate cancer, ECOG performance status, treatment regimen (ARTA vs ARTAs combination vs Taxanes vs ADT alone), major cardiac events (MACEs) rate after mCRPC treatment initiation, time to major cardiac events, family history of prostate cancer (yes vs no) and the number of relatives, family history of other malignancy, p53, pRB, PTEN mutation status if available.

Statistical Analysis Plan: The investigator seeks to analyze the impact of Androgen indifferent prostate cancer (AIPC) status on survival outcomes, namely overall survival and progression-free survival by means of the Cox regression or the Fine and Gray regression, if data on cancer specific mortality and other cause mortality is available, according to ARTAs-based treatment or chemotherapy regimens. Survival curves will be plotted according to the Kaplan-Meier method for overall survival and to the competing risks method for cancer specific mortality, if available. Moreover, intermediate clinical endpoints (ICEs) will be investigated, according to Prentice Criteria. Multivariable Cox regression analyses will be exploited to predict overall survival at different landmark points to evaluate the impact of the different intermediate endpoints.
Data on comorbidities, medical therapies at the time of randomization, survival and response outcomes will be necessary to carry out the proposed study.

Narrative Summary: Novel antiandrogen therapies have challenged the perception that most men with prostate cancer uniformly benefit from androgen ablation. The diverse responses to these recently approved therapies with distinct mechanisms of action (e.g., second-generation androgen or biosynthesis inhibitors) have exposed the biological heterogeneity of prostate cancer and illustrate the need to apply our understanding of prostate biology to clinical decisions. We would like to assess whether the clinical criteria of Aggressive Variant Prostate Cancer, a clinical entity that is considered androgen indifferent, truly identify poor responders to abiraterone, novel antiandrogen, or their combination.

Project Timeline: 12 months

Dissemination Plan: The study will be submitted to peer-reviewed journals for publication. Ideally on The Lancet Oncology or JAMA Oncology

Bibliography:

Berchuck et al. Prostate Cancer Prostatic Dis. 2021 September.
Spetsieris et al Cancers 2020 Disease.