ESMO 2018: STAMPEDE - Effects of Abiraterone Acetate plus Prednisone/Prednisolone in High and Low Risk Metastatic Hormone Sensitive Prostate Cancer

Munich, Germany ( Dr. Hoyle, on behalf of the STAMPEDE clinical trial group, presented the data on the effects of abiraterone acetate (AA) plus prednisone/prednisolone (P) [AAP] in high and low risk metastatic hormone sensitive prostate cancer (mHSPC). This is a very important presentation with significant clinical implications.

As background, in 2017, both STAMPEDE (abiraterone) and LATITUDE reported on the efficacy of AAP + ADT (androgen deprivation therapy) for mHSPC, demonstrating a significant survival benefit with the addition of AAP upfront at the time of diagnosis. This followed on the heels of CHAARTED data, which demonstrated survival benefit with the addition of 6 cycles of docetaxel with ADT in a similar patient population.

However, in the follow-up of those studies, some important distinctions were made:

  1. CHAARTED – there was an implication in the data that suggested that patients with “high volume” disease (visceral metastases or >=4 bone metastases) yielded more benefit than patients with “low volume” disease
  2. LATITUDE and STAMPEDE assessed two slightly different cohorts
            - LATITUDE was limited to cM1 patients (1199 patients included, HR 0.62)
            - STAMPEDE included cM0 and cM1 patients (1917 patients, HR 0.63)

Dr. Hoyle notes that when the STAMPEDE population is broken down into cM1 and cM0 populations, the following is noted:
  • cM1 population:  1002 patients, HR 0.61 – similar to LATITUDE
  • cM0 population:  915 patients, HR 0.75 (not clinically significant due to wider confidence interval). This suggests benefit, but perhaps not enough events
  1. The concept of “high risk” and “high volume” disease
- LATITUDE “high risk” included 2 of 3 high-risk features – Gleason 8-10, >= 3 bone mets, visceral metastases
- CHAARTED “high volume” based purely on disease burden - visceral metastases or >=4 bone metastases
- Which should be used? Does it matter?

The aim of this study was to assess whether AAP benefited “low risk” mHNPC. To do so, the authors retrospectively stratified the cM1 STAMPEDE patients into low/high risk (blinded to treatment arm) – primarily using LATITUDE criteria, but a secondary analysis was done using CHAARTED criteria.

The following demonstrates the breakdown of the 1002 patients with cM1 disease. Only patients from the UK were included so bone imaging could be assessed. After all exclusions applied, they ended up with 452 patients in the standard of care ADT arm and 449 patients in the SOC+AAP arm. 

First, they compared how many patients fit the LATITUDE and CHAARTED definitions. While 52.5% met LATITUDE high-risk and 55.4% met CHHARTED “high-volume” defintions, the following table demonstrates that the overlap is not perfect – 18.2% of patients would be classified differently based on the two different criteria!

UroToday ESMO2018 STAMPEDEa2

This highlights the importance of coming up with a standard definition for future studies.

He then delved into patient characteristics. Median follow-up now was 41.5 months. The demographics were as expected, and patients were evenly matched between groups. As expected, patients with high-risk disease had higher Gleason score, higher PSA and higher primary tumor stage.

UroToday ESMO2018 STAMPEDEa3

The following are the key outcomes based on LATITUDE risk stratification:
  1. When looking at survival outcomes, there was no difference in any survival outcome regardless of risk stratification. All favored AAP+ADT.

            - Overall survival:
                        - High risk: HR 0.54, p <0.001 – 3-year OS benefit 19.7%
                        - Low-risk: HR 0.66, p = 0.041 – 3-year OS benefit 4.4%
            - Failure-free survival:
                        - High-risk: HR 0.31, p <0.001
                        - Low-risk: HR 0.24, p <0.001
            - Progression-free survival:
                        - High-risk: HR 0.46, p <0.001
                        - Low-risk: HR 0.33, p <0.001
            - PCa-specific free survival:
                        - High-risk: HR 0.57, p <0.001 - 3-year CSS benefit 19.1%
                        - Low-risk: HR 0.51, p = 0.008 - 3-year CSS benefit 7.1%

The following diagram depicts this easily: 

UroToday ESMO2018 STAMPEDEa5
As a secondary analysis, they repeated this using CHAARTED risk stratification and found essentially the same results.
UroToday ESMO2018 STAMPEDEa6

Based on this, a retrospective analysis, they conclude that:
  1. There is significant individual risk stratification variation depending on the criteria utilized – 18.2% of patients would have been misclassified. A standardized risk stratifier is necessary.
  2. AAP+ADT improves all survival endpoints in mHNPC
  3. This is independent of risk stratification, so this applies equally to low and high-risk patients

Invited Discussant

Dr. Fizazi, the senior author of the LATITUDE trial, was an excellent invited discussant for this topic.

First, he again reviewed the literature for the current standard of care for mHNPC – either AAP+ADT or Docetaxel+ADT.
  • AAP+ADT – there are 2 studies (LATITUDE and STAMPEDE), which are both positive
    • On meta-analysis, 38% reduction in death
      • Higher chance to be T-eff high or PD-L1+
    • On meta-analysis, 23% reduction in death

He covered much of the same material as Dr. Hoyle, which I won’t repeat here. However, he did make a few additional points that should be highlighted.
  1. ASCO 2018 Fizazi et al. – Longer follow-up of the LATITUDE trial confirmed OS benefit with AAP+ADT. HR 0.64, p < 0.0001. Median follow-up now 41 months (similar to STAMPEDE study)
  2. The main limitations of the current presentation are that this is a retrospective study in a post-hoc, non-pre-planned analysis. It is also underpowered (~200 patients/group). The authors acknowledged these limitation.
  3. Regardless, this is very important information! Likely with this information, the new SOC for low-risk mHNPC should be AAP. For high-risk, it can be either AAP+ADT or Doc+ADT.

He did allude to the fact that AAP is an expensive treatment option – but will be a generic option in 2019. This may open up utilization in more parts of the world for more patients.

Presented By: Alex P. Hoyle, MBChB, MRCS, The Christie and Salford Royal Hospitals, Manchester, United Kingdom
Invited Discussant: Karim Fizazi, MD, Ph.D., Medical Oncologist, Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France and Professor in Oncology at the University of Paris

CHAARTED: Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
STAMPEDE: 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.
LATITUDE: 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.

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, twitter: @tchandra_uromd, @TjuUrology at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany