AUA 2018: Phase 3 Study of Intermittent Monotherapy Versus Continuous Combined Androgen Deprivation

San Francisco, CA (UroToday.com) In this abstract, the authors presented updated results of the South European UroOncology Group (SEUG) 9901 randomized controlled trial, initially published in 2014.1 In the original publication, the authors completed a randomized phase III non-inferiority trial comparing intermittent hormone therapy with cyproterone acetate (CPA) to continuous maximal androgen blockade (MAB) in patients with advanced/metastatic prostate cancer. All patients received induction with LHRH (triptoreline) agonist and CPA. In patients whose PSA < 4 after 3 months induction, patients were randomized to either intermittent CPA (stopped therapy, started CPA when PSA > 20) or continuous MAB. Ultimately, they found that patients on intermittent therapy had non-inferior overall survival (HR 0.9, p=0.99) or progression-free survival, and patients on intermittent had better sexual function than those on MAB. This is consistent with data from other intermittent therapy studies. 

However, the median follow-up of the original study was 66 months (5.5 years). In this follow-up abstract, median follow-up is now 5.8 years, which is not much different than previously! However, maximal follow-up has increased from 12 years to 17 years.

The median PSA at randomization was 1.0ng/ml, but it ranged from 0.1 to 9. 49. 214 patients were still alive more than 10 years following randomization,107 on Intermittent CPA and 107 on MAB. A total of 658 (331 Intermittent, 327 Continuous) patients have died; 208 of these patients died from prostate cancer (106 Int. and 102 MAB). 

Overall survival analysis: Metastatic status, PSA, and age at randomization are all prognostic factors for survival. M1 patients have an increased risk of dying (HR=1.64, 95% CI 1.28, 2.09) and there is a trend for an increased hazard of death with increasing age so that men aged 75+ have a hazard ratio of 1.79 (95% CI 1.21, 2.66) compared to men aged under 60. Men whose PSA falls to between 2 and 4 have an increased hazard of dying relative to those whose PSA falls below 0.5 (HR=1.86, 95% CI 1.52, 2.27). 

Most importantly, the authors state that adjusting for Age, PSA nadir and metastatic status, patients on Intermittent therapy had a reduced hazard of death compared to Continuous therapy (HR 0.92, p=0.27) – yet this is not significant at all. Nor would I count this as a trend. 

From a non-prostate cancer death standpoint, There are no differences in cause-specific hazards of death though there is a slight tendency to have slightly poorer survival on Continuous therapy driven largely by elevated cardiovascular deaths. There is no difference in prostate cancer deaths, though those randomized to Intermittent therapy have a higher hazard of a death due to non-prostate cancer.

However, this was still powered as a non-inferiority trial, so we cannot say it is better than MAB. 

As intermittent therapy has become more accepted, this trial continues to add evidence to support its use. While different studies have utilized agents for intermittent therapy, the overwhelming evidence suggests it is non-inferior to continuous therapy with preservation of function. 

During the discussion, a few important points come up:

1. This is essentially a non-inferiority study – as there was no difference in outcomes.
2. The trend for more PCa-specific deaths in the intermittent arm and non-PCa-specific deaths in the continuous arm. Therefore, perhaps risk stratification will identify which patients benefit from a PCa-specific standpoint?
3. Dr. Calais da Silva stated his take-home stratification is that intermittent should be considered if PSA < 4 (especially if <1.0), but should not be considered if PSA never drops below 4.0. 
4. CPA is not approved in the United States however, bicalutamide is. Prior data shows that bicalutamide may be more effective and associated with less cardiovascular toxicities than CPA – so perhaps this may be a better option? The presenter agreed with this statement and felt intermittent therapy with either agent would be effective.


Presented by: Fernando Calais da Silva Junior, MD
Co-Authors: Fernando Calais da Silva Senior, Lisboa, Portugal, Frederico Gonçalves, Bratislava, Slovakia (Slovak Republic), Jan Kliment, Martin, Slovakia (Slovak Republic), Américo Santos, Braga, Portugal, Spiros Pastidis, Athens, Greece, Antonio Queimadelos, Santiago Compostela, Spain, Chris Robertson, Glasgow, United Kingdom

References:
1. Calais da Silva F et al. Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European Uroncological Group. Eur Urol. 2014 Aug;66(2):232-9. doi: 10.1016/j.eururo.2013.03.055. Epub 2013 Apr 4.

Written by:  Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, | twitter: @tchandra_uromd at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA
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