ESMO 2022: Additional Insights from the STAMPEDE Trial Platform

(UroToday.com) The 2022 ESMO annual meeting featured a prostate cancer session, including a discussant presentation by Dr. Elena Castro discussing two key studies from the STAMPEDE trial platform, including “Comparison of abiraterone acetate and prednisolone or combination enzalutamide + abiraterone acetate and prednisolone for mHSPC starting ADT: OS results of 2 randomized Phase III trials from the STAMPEDE protocol” presented by Dr. Gerhardt Attard, and “Clinical qualification of transcriptome signatures for advanced prostate cancer starting ADT with or without abiraterone acetate and prednisolone: an ancillary study of the STAMPEDE AAP trial” presented by Dr. Marina Parry. Dr. Castro started her presentation by highlighting that there are multiple treatment options available for mHSPC:

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More recently, we have seen improved OS in mHSPC with further intensified therapy based on triplet therapy data from PEACE-11 and ARASENS2:

STAMPEDE AAP-1.jpg

Based on data presented at ESMO 2022 from Attard et al. there was an OS benefit in abiraterone acetate and prednisolone + enzalutamide trial (HR 0.65, 95% CI 0.55‒0.77), as well as a metastatic progression free survival benefit (HR 0.52, 95% CI 0.44‒0.68):

STAMPEDE AAP-2.jpg

Additionally, Dr. Castro notes that this study also showed that at 7 years in abiraterone acetate and prednisolone trial (median follow-up: 95.8 months), 30% (95% CI 26, 34) patients were alive with ADT versus 48% (95% CI 43, 52) with ADT + abiraterone acetate and prednisolone. Restricted mean survival times were 50.4 months with ADT alone versus 60.6 months with ADT + abiraterone acetate and prednisolone (p = 6.6 x 10-9):

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However, it is important to note that the addition of enzalutamide to abiraterone acetate + prednisolone does not improve OS in de novo mHSPC: 

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Furthermore, the addition of enzalutamide to abiraterone acetate + prednisolone does lead to increased toxicity, particularly increased cardiac toxicity. Dr. Castro notes that previous studies have also suggested futility when combining novel hormonal therapies compared to monotherapy, as has been shown in ACIS, Alliance A031201, and PLATO: 

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Shifting to discuss the study presented by Parry et al., Dr. Castro highlighted that none of the transcriptomic signatures (AR-A, PAM50, PSC, and the Decipher genomic classifier) were predictive of treatment effect of abiraterone acetate + prednisolone on OS. However, the Decipher genomic classifier was strongly prognostic in advanced prostate cancer (per 0.1 increment, M1 OS (HR 1.18, 95% CI 1.09 - 1.26, p < 0.001), much like as it has previously been shown for docetaxel in the CHAARTED trial:3 

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A high Decipher genomic classifier score was also associated with shorter MFS in high-risk localized prostate cancer (HR 1.20, 95% CI 1.09 - 1.31, p < 0.001) suggesting that these patients may also benefit from abiraterone acetate + prednisolone:

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Dr. Castro also highlighted that the work from Parry and colleagues also showed that prognostic signatures are different in M0 and M1 patients, with the following showing testing of 54 signatures for association with outcome (MFS in M0 and OS in M1, p < 0.001):

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To conclude, Dr. Castro notes that one of the main challenges of precision oncology in prostate cancer is sample analysis. In the STAMPEDE trial, less than 50% of patients were able to have transcriptomic analysis successfully, however, she notes that this is not unique to STAMPEDE, given that previous issues have been reported in PROfound (31% not evaluable), TRITON2 (32% not evaluable), and IPATential150 (33% not evaluable).  

Presented by: Elena Castro, MD, Hospital Universitario, Madrid, Spain

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 European Society of Medical Oncology (ESMO) Annual Hybrid Meeting, Paris, FR, Fri, Sept 9 – Tues, Sept 13, 2022.

References:

  1. Fizazi K, Foulon S, Carles J, Roubaud G, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): A multicentre, open-label, randomized, phase 3 study with a 2 x 2 factorial design. Lancet. 2022 Apr 30;399(10336):1695-1707.
  2. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022 Mar 24;386(12):1132-1142.
  3. Hamid AA, Huang HC, Wang V, et al. Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: Correlative analysis of the E3805 CHAARTED trial. Ann Oncol. 2021 Sep;32(9):1157-1166.
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