AUA 2018: Predictors of Radiographic Progression in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Abiraterone: Retrospective Analysis of COU-AA-302

San Francisco, CA (UroToday.com) The management of advanced prostate continues to change rapidly. The introduction of androgen targeted therapy was a major advance in the management of this disease state, and abiraterone acetate (AA) and enzalutamide have led the way. The COU-AA-302 trial1 was the second randomized trial of AA vs placebo and specifically looked at patients who were chemotherapy naïve. In this placebo-controlled, double-blind, randomized phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer were randomized to either AA+prednisone or prednisone alone. At a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033).

In this abstract, the authors were able to obtain the data from the clinical study through the Yale Open Data Access Project. They specifically assessed the dataset looking for predictors of radiographic progression in this patient population of men treated with AA (n=546) By doing so, they hoped to find patterns that could help inform us about the optimal frequency of imaging in mCRPC men, as repeated imaging is costly and access may be limited. 

The primary outcome measure was the time from randomization to radiographic progression in bone and/or soft tissue (n=301 events). After initial univariate and multivariable analyses to identify predictors of recurrence, they used two different methods to evaluate these patients:

1. An MV model was used to generate a risk score. The risk score was then used to separate patients into tertiles – low, intermediate, and high risk.
2. The two most predominant predictors on MV analysis were used as a model to stratify patients into 6 strata. 

The median time to radiographic progression was 16.6 months (approximately 1.5 years). 

In the first analysis, using a model containing baseline variables (extent of disease, ECOG status, pain, prostate-specific antigen (PSA), lactate dehydrogenase, alkaline phosphate (ALP) and albumin) and change in PSA and ALP at 8 weeks (two variables most predictive of recurrence) had a concordance statistic of 0.71. The three tertiles based on risk score were able to discriminate risk of progression quite well.

The extent of disease at baseline and change in PSA at 8 weeks were the strongest independent determinants of recurrence/progression-free survival (RPFS). These were used to generate the second model. Using these two variables, patients were grouped into 6 strata, which correlated with the probability of RPFS at 6 and 12 months. In men with bone-only disease at baseline and a >= 50% fall in PSA (32% of all subjects, lowest risk stratum), RPFS was 93% (95% CI 87 to 96) at 6 months and 80% (95% CI 72 to 86) at 12 months. In contrast, the probability of RPFS for men with bone and soft metastasis at baseline and < 50% fall in PSA (13% of all subjects, highest risk stratum) was 55% (95% CI 41 to 67) at 6 months and 34% (95% CI 22 to 47) at 12 months.

Using this relatively straightforward risk stratification (extent of disease and %PSA response) rather than a more complex model using all the variables, the authors conclude that these results suggest that the imaging schedule for men mCRPC can be personalized. However, these findings need to be externally validated, and examined with other treatments, and may ultimately lead to more efficient use of imaging in men with mCRPC.

This presentation generated some important questions:
1. Fred Saad, MD noted that PSA alone, as a single variable, may be able to give similar discriminatory ability. He asked if this was explored as an option. Lisa Martin, MD did note that the current 2-variable model was better than PSA alone, but did not go into further details.
2. Another important point is that the COU-AA-302 study classified nodal disease as soft tissue disease – not visceral metastases. Thus, the fact that patients with bone mets alone do better than patients with soft tissue disease contrasts with intuition. There was no great explanation for this finding. 


Presented by: Lisa Martin, Ph.D.Princess Margaret Cancer Centre/University Health Network
Co-Authors: Shabbir Alibhai, Maria Komisarenko, Narhari Timilshina, Antonio Finelli, Princess Margaret Cancer Centre, University of Toronto

References:
1. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. doi: 10.1016/S1470-2045(14)71205-7. Epub 2015 Jan 16.

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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