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  ["project_title"]=>
  string(84) "PSA Progression in High-Risk Metastatic Castration-Sensitive Prostate Cancer (mCSPC)"
  ["project_narrative_summary"]=>
  string(688) "The assessment of treatment efficacy in mCSPC is hindered by the fact that response to primary ADT is achieved in an overwhelming majority of patients. A number of alternative PSA response measures have been studied. The clinical significance of PSA progression is however unclear, especially in the absence of clinical/radiographic progression. Trials did not mandate treatment discontinuation based on PSA progression; its significance is, therefore, unknown. 

We aim to evaluate the clinical significance of a PSA progression in patients from the LATITUDE study, as well as clinical features that may help identify patients at a high risk of clinical or radiographic progression."
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    ["value"]=>
    string(68) "No external grants or funds are being used to support this research."
    ["label"]=>
    string(68) "No external grants or funds are being used to support this research."
  }
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      ["post_title"]=>
      string(257) "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)"
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      string(193) "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-h"
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      ["post_modified"]=>
      string(19) "2023-02-06 13:28:21"
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      string(242) "https://dev-yoda.pantheonsite.io/clinical-trial/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-h/"
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  ["project_date_type"]=>
  string(91) "Individual Participant-Level Data, which includes Full CSR and all supporting documentation"
  ["property_scientific_abstract"]=>
  string(1585) "Background: PSA progression (PSAProg) at 7 months has been associated with decreased overall survival in mCSPC patients treated with ADT in the SWOG 9346 trial. Abiraterone acetate has been shown to significantly prolong survival in combination with ADT in patients with mCSPC in the LATITUDE trial; patients on PSA progression only were allowed to continue on study. The clinical significance of PSA progression in mCSPC patients is poorly understood.

Objective: to evaluate the incidence, prognostic significance and factors associated with PSAprog in high-risk mCSPC patients.

Study Design: retrospective cohort study.

Participants: mCSPC patients treated in the LATITUDE trial, with a baseline and at least one post-treatment PSA value.

Main Outcome Measures: Overall survival.

Statistical Analysis: The proportion of patients experiencing PSAprog at pre-specified timepoints will be calculated. Uni- and multivariable Cox proportional hazards models will be used to evaluate the association of PSAprog and OS, rPFS, cPFS and time to QoL deterioration. Time from PSAprog only to radiographic/clinical progression or death will be calculated. Uni- and multivariable Cox proportional hazards (PH) models will be used to evaluate factors associated with time to rPFS / cPFS. Known prognostic clinical factors will be included as covariates in each of the Cox-PH models. The performance of the models will be evaluated by calculating the c-indices. Analyses will be performed in all subjects, and separately in the abiraterone and placebo-treated cohorts."
  ["project_brief_bg"]=>
  string(3173) "Although metastatic, castration-sensitive prostate cancer represents only 3% of new prostate cancer diagnoses in the United States,1 it is the form of presentation in approximately half of patients that ultimately die from the disease.2 Traditionally, treatment for mCSPC was based on androgen deprivation therapy through orchiectomy or GnRH analogues, with contemporary series reporting a median 11 month failure-free survival, and median overall survival of 42 months.3

In recent years, several phase III trials have reported a significant improvement in overall survival with the addition of docetaxel to ADT (GETUG-AFU-15, CHAARTED, STAMPEDE),4?6 followed by trials evaluating ADT + abiraterone (LATITUDE, STAMPEDE)7,8 and, more recently, trials evaluating apalutamide (TITAN)9 and enzalutamide (ENZAMET, ARCHES),10,11 setting new therapy standards for the disease.

The randomized, double-blind, placebo-controlled LATITUDE study compared efficacy and safety of abiraterone + prednisone + ADT with placebo + ADT in men with high-risk mCSPC, demonstrating significantly longer overall survival (OS) and radiographic progression-free survival (rPFS).7 In a recently published post-hoc analysis of the LATITUDE trial, the association of a PSA response (50% or 90% decline from baseline), rates of PSA < 0.2 ng/mL, nadir PSA, time to PSA progression and time to PSA nadir were all found to be significantly associated with radiographic progression-free survival and overall survival.7 

In mCSPC, the impact of PSA progression is less-well known. In the SWOG 9346 trial, the association of PSA progression at any time and OS, and between PSA progression status at 7 months and survival was evaluated. Both PSA progression endpoints were associated with a > 4 times increase in the risk of death; median subsequent OS was 10 months versus 44 months in patients who did or did not have PSA progression by 7 months.12

To our knowledge, no study has yet reported rates of primary PSA progression, or analysed the significance of an exclusive PSA (without radiographic) progression in mCSPC patients. Specific data on the natural history of patients experiencing PSA-only progression are also lacking.

We aim to:

(a) Determine the incidence, prognostic significance and factors associated with a PSA-only progression, either primary (at 7 months after treatment initiation) or secondary (after PSA response, or a lack of progression at 7 months) in mCSPC patients treated with abiraterone + prednisone or placebo + prednisone.

(b) Compare the prognostic ability of PSA progression measures with other PSA response measures

(c) Determine the time elapsed between PSA progression and clinical/radiographic progression or death, as well as clinical factors associated with time between PSA progression and radiographic/clinical progression.

We anticipate our results will help clinicians perform better informed decision-making in patients with PSA progression on abiraterone for mCSPC, by enabling clinicians to identify patients at a high risk of clinical or radiographic progression, that may benefit from a treatment switch."
  ["project_specific_aims"]=>
  string(1262) "Overall Aims:

-	To validate the prognostic impact of PSA progression at 7 months (PSA-P) after treatment initiation in metastatic hormone-sensitive prostate cancer.

Specific Endpoints:

Primary Endpoint:

-	Association between PSA-P and overall survival

Secondary Endpoints:

-	Factors associated with overall survival at the time of PSA progression.

-	Association between PSA-P and radiographic progression-free survival.

-	Time from PSA progression to radiographic progression

o	Proportion of patients with and without visceral disease progression.

-	Time from PSA progression to:

o	Subsequent therapy initiation

o	Pain progression

o	QoL deterioration

o	Skeletal-related events

-	Proportion of patients with (at the time of PSA progression):

o	PSA progression exclusively

o	PSA + radiographic progression

o	PSA + radiographic + clinical progression

-	Association between PSA-P at 12, 18 and 24 months with overall survival, radiographic progression-free survival and time to QoL deterioration.

Exploratory Endpoints:

-	Comparison of PSA progression with other PSA-derived endpoints (90% PSA response, 50% PSA response, PSA < 0.02 ng/mL)."
  ["project_study_design"]=>
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  ["project_study_design_exp"]=>
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  ["project_purposes"]=>
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      ["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"
    }
  }
  ["project_purposes_exp"]=>
  string(0) ""
  ["project_software_used"]=>
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    ["value"]=>
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    ["label"]=>
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  ["project_research_methods"]=>
  string(278) "Data Source: LATITUDE trial dataset

Inclusion Criteria:

Patients treated with ADT + abiraterone + prednisone or ADT + placebo + prednisone in the LATITUDE trial

Survival >= 12 weeks.

Baseline PSA value and at least one post-treatment PSA value available."
  ["project_main_outcome_measure"]=>
  string(1002) "Main Outcome Measure

Overall survival, defined as the time (months) from PSA progression to death.

Secondary Outcome Measures

- Radiographic progression-free survival (rPFS), which will be defined as the time from PSA progression to radiographic progression or death

- Clinical progression-free survival (cPFS) or death, which will be defined as the time from PSA progression to clinical progression, in months.

- Time to quality of life deterioration will be defined as the time from PSA progression to clinically significant FACT-P or BPI-SF progression.

Radiographic and clinical progression will be defined according to the definitions established in the LATITUDE trial protocol. 

Quality of Life / Patient Reported Outcomes: quality of life will be quantified according to BPI-SF and FACT-P questionnaire results. Thresholds for clinically significant BPI-SF progression and/or FACT-P progression will be defined per criteria from LATITUDE trial protocol."
  ["project_main_predictor_indep"]=>
  string(382) "PSA progression will be defined according to PCWG3 guidelines as a ?25% and ? 2 ng/mL increase from baseline (if no initial PSA decline is observed), or a ?25% and ? 2 ng/mL increase above the nadir (if an initial PSA decline is observed), confirmed by a second value ? 3 weeks later. Time to PSA progression will be defined as the time from treatment initiation to PSA progression."
  ["project_other_variables_interest"]=>
  string(725) "Baseline variables:

- Treatment arm: categorical

- Ethnicity: categorical

- Age, height, weight: continuous

- Type of disease progression at baseline: categorical

- Time from LHRH treatment to trial treatment initiation

- Presence of bone, node, liver, other visceral metastases: yes/no

- Gleason Score: ordinal

- Prior surgery or radiation therapy to primary: yes/no

Baseline and at post-baseline time-points:

- Hemoglobin, albumin, alkaline phosphatase, LDH, PSA: continuous.

- ECOG PS: ordinal (0-4)

- BPI-SF score, analgesic score (continuous)

- FACT-P score (continuous)

- Post-baseline radiographic evaluation (BS/CT scan): categorical"
  ["project_stat_analysis_plan"]=>
  string(825) "- A descriptive analysis of endpoints and baseline covariates will be performed. Results will be presented as the median and interquartile range (IQR) for continuous variables and as number and percentage frequency for categorical variables.

- Logistic regression models will be used to determine the association between PSA progression and the different baseline variables. Odds ratio estimates and 95% confidence intervals will be calculated.

- The Kaplan-Meier method will be used to estimate median survival times (OS, rPFS, cPFS) and 95% confidence intervals, in months.

- Cox proportional-hazards (Cox-PH) models will be used to test the association of PSA progression with overall survival, progression-free survival and clinical progression-free survival. Other covariates that show a significant (p"
  ["project_timeline"]=>
  string(249) "- Project submission: April 2020

- Contract: April-May 2020

- Analysis: June-November 2020

- Abstract Submission (ASCO GU 2021): October 2020 - Paper Draft circulation: January-February 2021

- Paper Submission: April-May 2021"
  ["project_dissemination_plan"]=>
  string(169) "- Abstract presentation in ASCO GU 2021

- Submission of manuscript first-quartile oncology journals: Annals of Oncology, European Urology, Clinical Cancer Research"
  ["project_bibliography"]=>
  string(2760) "
1. 	Weiner AB, Matulewicz RS, Eggener SE, Schaeffer EM. Increasing incidence of metastatic prostate cancer in the United States (2004?2013). Prostate Cancer Prostatic Dis. 2016;19(4):395-397. doi:10.1038/pcan.2016.30

2. 	Patrikidou A, Loriot Y, Eymard J-C, et al. Who dies from prostate cancer? Prostate Cancer Prostatic Dis. 2014;17(4):348-352. doi:10.1038/pcan.2014.35

3. 	James ND, Spears MR, Clarke NW, et al. Survival with newly diagnosed metastatic prostate cancer in the docetaxel era: Data from 917 patients in the control arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). Eur Urol. 2015;67(6):1028-1038. doi:10.1016/j.eururo.2014.09.032

4. 	Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): A randomised, Open-label, Phase 3 trial. Lancet Oncol. 2013;14(2):149-158. doi:10.1016/S1470-2045(12)70560-0

5. 	Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747

6. 	James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2015;6736(15):1-15. doi:10.1016/S0140-6736(15)01037-5

7. 	Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174

8. 	James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900

9. 	Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307

10. 	Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835

11. 	Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799

12. 	Hussain M, Goldman B, Tangen C, et al. Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. J Clin Oncol. 2009;27(15):2450-2456. doi:10.1200/JCO.2008.19.9810
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