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

Lead Investigator: Daniele Robesti, Ospedale San Raffaele
Title of Proposal Research: Assessing the Androgen indifferent prostate cancer patients reponse to novel antiandrogen-based regimen or taxanes.
Vivli Data Request: 8722
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Androgens are hormones that are important for normal male sexual development. Androgen receptors allow the body to respond appropriately to these hormones. Testosterone is an androgen that promotes prostate cancer cell proliferation through the activation of androgen receptor. Both players are needed for cell proliferation in prostate cancer cells. For these reasons, testosterone and its receptor, namely, the Androgen Receptor (AR) have been targetted for impairing prostate cancer growth and progression. However, the recent development of novel anti-androgen therapies (ARTAs) has challenged the perception that prostate cancer proliferation and progression always depend on these two players alone. The diverse responses to these recently approved therapies with distinct mechanisms of action have exposed the biological heterogeneity/diversity of prostate cancer cells and illustrated 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 to define those prostate cancer phenotypes (the set of observable characteristics or traits of an organism) that do not depend on testosterone and AR to proliferate and progress. The AIPC entity is an umbrella term that includes several clinical entities. Among these entities, the investigator will focus on the one called Aggressive Variant Prostate Cancer (AVPC).

Since the ARTAs introduction and extensive use in prostate cancer, the androgen indifferent phenotype is becoming an increasingly common clinically meaningful entity. Among these clinical entities, the investigators will explore whether the clinical criteria for AVPC, truly identify patients not responding to novel anti-androgen therapies (ARTAs), their combinations, or androgen deprivation therapy alone. We will study AVPC as this is the most aggressive form of advanced prostate cancer, as its name suggests. The identification of the AVPC phenotype based on clinical criteria may potentially spare patients from potential side effects related to these therapies targeting androgen receptor, such as major cardiac events (MACES).

The results of our work may affect clinical trial inclusion criteria, sparing AIPC/AVPC patients from receiving AR targeting agents.

In case these clinical criteria fail to identify the refractory phenotypes, the analysis on the most informative intermediate clinical endpoint may expedite future clinical trial by shortening the required follow-up of future studies.

Statistical Analysis Plan:

The overall population of the requested studies will be split into four groups based on the treatment regimens (ADT alone, vs ARTAs, vs ARTA combination, vs Taxanes-based chemotherapy). The impact of AIPC status will be evaluated for each treatment regimen. All the requested studies deal with metastatic prostate cancer, a unique disease setting.

To maintain the structure and independence of the requested studies, a systematic and rigorous approach will be employed in the analysis, ensuring that the individual studies are treated as separate entities rather than combined into a single dataset. The following methods will be utilized:
1) Subgroup Analysis: If there are distinct subgroups within the selected studies, separate analyses will be conducted for each subgroup to explore any potential differences or unique patterns. This approach allows for the independent examination of various factors and helps maintain the independence of the individual studies. This will be performed for de novo metastatic prostate cancer vs metachronous prostate cancer. Similarly, patients receiving fist line treatment will be considered separately from those receiving second and third line treatments.
2) Sensitivity Analysis: Sensitivity analyses will be performed to assess the robustness of the results by evaluating the impact of excluding certain studies or examining the influence of different analytical approaches. This analysis will help ensure that the findings are not solely driven by a single study or methodological choice. For instance, study administering ARTAs sequentially may be excluded from the sensitivity analysis.
3) Data Extraction: From each selected study, relevant data will be extracted using a standardized data extraction form. The extracted data will include key variables, patient characteristics, treatment regimens, outcomes, and any other pertinent information specific to the research question, such as AVPC phenotype vs no AVPC phenotype.

The survival outcomes considered are overall survival, progression-free survival (analyzed by means of the Cox regression), and cancer-specific mortality and other cause mortality (analyzed by means of the Fine and Gray regression. Survival curves will be plotted according to the Kaplan-Meier method for overall survival and progression-free survival, and according to the competing risks method for cancer-specific mortality. 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, and survival and response outcomes will be necessary to carry out the proposed study.

Requested Studies:

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
Data Contributor: Johnson & Johnson
Study ID: NCT01591122
Sponsor ID: CR100011

Randomized, Open Label Multi-Center Study Comparing Cabazitaxel at 20 mg/m² and at 25 mg/m² Every 3 Weeks in Combination With Prednisone for the Treatment of Metastatic Castration Resistant Prostate Cancer Previously Treated With a Docetaxel-Containing Regimen
Data Contributor: Sanofi
Study ID: NCT01308580
Sponsor ID: EFC11785

Multicentre, Single-arm, Open Label Clinical Trial Intended to Provide Early Access to Cabazitaxel in Patients With Metastatic Hormone Refractory Prostate Cancer Previously Treated With a Docetaxel-containing Regimen and to Document Safety of Cabazitaxel in These Patients
Data Contributor: Sanofi
Study ID: NCT01254279
Sponsor ID: CABAZ_C_05331

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
Data Contributor: Johnson & Johnson
Study ID: NCT00887198
Sponsor ID: CR016927

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
Data Contributor: Johnson & Johnson
Study ID: NCT01867710
Sponsor ID: CR100916

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
Data Contributor: Johnson & Johnson
Study ID: NCT00638690
Sponsor ID: CR016924

Summary of Results:

Most of the issues are related to the missing data to correctly identify aggressive variant prostate cancer patients per clinical criteria. In particular no data were available regarding lytic bone metastasis, presence of neuroendocrine markers, information regarding bulky lympadenopathies, time to progression to castration-resistant status was missing. Therefore, we were not able to create the independent variable “Androgen indifferent prostate cancer” (yes vs no) for the whole cohort.