ESMO 2022: 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

(UroToday.com) The 2022 ESMO annual meeting featured a prostate cancer session, including a presentation by Dr. Gerhardt Attard discussing a comparison of abiraterone acetate and prednisolone or combination enzalutamide + abiraterone acetate and prednisolone for mHSPC starting ADT. Previous studies note that abiraterone acetate and prednisolone or enzalutamide added to ADT improves outcomes for mHSPC. Combining enzalutamide and abiraterone acetate and prednisolone may improve rPFS in mCRPC but no discernible improvement in OS and the benefit in mHSPC is uncertain. Furthermore, survival outcomes of metastatic prostate cancer started on ADT + 2nd generation hormonal agent after >5 years have not been reported.

STAMPEDE is a multi-arm, multi-stage, platform protocol conducted at 117 sites in the UK & Switzerland. There were 2 trials with no overlapping controls that randomized mHSPC patients 1:1 to ADT +/- abiraterone acetate and prednisolone (1000mg od abiraterone acetate + 5mg od prednisolone) or abiraterone acetate and prednisolone + enzalutamide (160mg od):

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Treatment was continued to progression. From January 2016 docetaxel 75mg/m2 3-weekly with prednisolone 10mg od was permitted + ADT. Using meta-analysis methods, Dr. Attard and colleagues tested for evidence of a difference in OS and secondary outcomes (as described previously: failure-free, metastatic progression-free, progression-free & prostate cancer specific survival) across the 2 trials using data frozen July 3, 2022. Restricted mean survival times restricted to 84 months.

 Between November 2011 and January 2014, 1,003 patients were randomized to ADT +/- abiraterone acetate and prednisolone, and between July 2014 and March 2016, 916 patients were randomized to ADT +/- abiraterone acetate and prednisolone + enzalutamide. Randomized groups were well balanced across both trials. The median patient age was 68 years (IQR 63, 72), the median PSA prior to ADT was 96 ng/ml (IQR 26, 346), 94% of patients were de novo, and 6% of patients relapsed after radical treatment. In the abiraterone acetate and prednisolone + enzalutamide trial, 9% had docetaxel + ADT. The median follow-up in the ADT +/- abiraterone acetate and prednisolone trial was 95.8 months and 71.7 months in the ADT +/- abiraterone acetate and prednisolone + enzalutamide trial. There was an OS benefit in abiraterone acetate and prednisolone + enzalutamide trial (HR 0.65, 95% CI 0.55‒0.77, p = 1.4×10-6), as well as in the abiraterone acetate and prednisolone trial (HR 0.62, 95% CI 0.53-0.73, p = 1.6×10-9):

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There was no evidence of a difference in treatment effect (interaction HR 1.05, 95% CI 0.83‒1.32, p = 0.71) or between-trial heterogeneity (I2 p = 0.70). As follows are the subgroup analyses for OS:

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For the planned OS subgroup analysis for docetaxel, there was a non-statistically significant interaction for effect (HR 0.81, 95% CI 0.50-1.32, p = 0.384). With regards to metastatic progression free survival, there was a benefit in abiraterone acetate and prednisolone + enzalutamide trial (HR 0.52, 95% CI 0.44‒0.68), as well as in the abiraterone acetate and prednisolone trial (HR 0.50, 95% CI 0.43‒0.58):

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The percentage of patients reporting grade 3-5 toxicity in the first 5-years was as follows:

  • Abiraterone acetate and prednisolone trial, ADT alone: 38.5%, 95% CI 34.2-42.8
  • Abiraterone acetate and prednisolone: 54.4%, 95% CI 50.0-58.8
  • Abiraterone acetate and prednisolone + enzalutamide trial, ADT alone: 45.2%, 95% CI 40.6 – 49.8
  • Abiraterone acetate and prednisolone + enzalutamide: 67.9%, 95% CI 63.5 – 72.2

The most frequent adverse events were with abiraterone acetate and prednisolone or abiraterone acetate and prednisolone + enzalutamide, including liver derangement and hypertension. As follows are a summary of the grade 5 adverse events, specifically noting the cardiac adverse events in the abiraterone acetate and prednisolone + enzalutamide treated patients:

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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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Dr. Attard concluded his presentation discussing a comparison of abiraterone acetate and prednisolone or combination enzalutamide + abiraterone acetate and prednisolone for mHSPC starting ADT with the following take-home messages:

  • Enzalutamide + abiraterone acetate and prednisolone need not be combined for mHSPC (nor for high-risk localized prostate cancer)
  • Clinically important improvements in OS when adding abiraterone acetate and prednisolone to ADT are maintained at 7 years

Additionally, Dr. Attard noted several limitations and future directions:

  • Indirect comparison of 2 trials (unlikely to have missed an effect size of interest)
  • No comparison with ADT + enzalutamide (considered unlikely to be notably different)
  • Further treatment combinations will require patient selection and splitting of mHSPC (ie. by volume of disease)

Presented by: Gerhardt Attard, MD, PhD, Research Department of Oncology, UCL Cancer Institute - UCL - London's Global University, London, UK

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 2022 European Society of Medical Oncology (ESMO) Annual Hybrid Meeting, Paris, FR, Fri, Sept 9 – Tues, Sept 13, 2022. 

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