As the authors note, the TOAD trial,1 found an overall survival benefit for immediate compared to delayed ADT for PSA-relapsed or non-curable prostate cancer (5-year OS 91% for immediate vs. 86% in delayed ADT, p = 0.047). This study is also previously discussed in a Beyond the Abstract commentary on Urotoday.
Some issues that were brought up in this presentation regarding the TOAD trial include:
- Only 293 of planned 750 patients included
- Survival benefit was not demonstrated in PSA-relapse subgroup (p=0.10)
- Pertinent: Up to 12 months of prior ADT allowed
However, the trial’s broad eligibility criteria (any man with PSA relapse after prior attempted curative therapy OR if not considered suitable for curative treatment) allowed entry of a heterogeneous group of participants, including those with prior ADT exposure. The authors of this study raised concerns about subsequent androgen-sensitivity in patients with prior ADT exposure, and for these reasons, they conducted sub-group analyses using trial data to assess if prior ADT was associated with the subsequent efficacy of ADT timing after PSA relapse.
Utilizing the clinical trial data, Stensland et al. examined patient-level data for participants with PSA relapse after prior definitive local therapy (as the other cohort of patients who were not eligible for curative therapy would not have been exposed to ADT). They then performed Kaplan-Meier analyses for overall survival (the primary outcome of the study) stratified by prior ADT and randomized treatment arm (immediate or delayed ADT). They compared characteristics between subgroups and examined the effect of prior ADT on overall survival using multivariable Cox proportional hazards models.
Looking at the patient data, they identified 261 patients with PSA-relapse – when looking at ADT exposure, the breakdown was as follows:
- No prior ADT: 68 delayed, 69 immediate ADT
- Prior ADT: 69 delayed, 55 immediate ADT
- p=0.40 – no significant difference between cohorts
When comparing the groups:
- Patients with prior ADT had slightly higher PSA at presentation (12.05 vs. 9.00, p <0.001)
- Patients with prior ADT were more likely to have received radiotherapy as local treatment (79.8% vs 48.2%, p <0.001)
- Patients with prior ADT were more likely to have cT3 disease
When looking at outcomes, they found that patients with prior ADT who received immediate ADT had better overall survival compared to other groups (p=0.02, Figure 1a). More importantly, they note that the benefit of immediate vs. delayed ADT was seen in the prior ADT group (p=0.004, Figure 1b), but not in the no prior ADT group (p=0.82, Figure 1c).
This was supported on multivariable analysis, as the only association with overall survival was the immediate treatment X prior ADT interaction term (HR 0.13 [95% CI 0.02-0.73], p=0.02). A similar pattern was found for prostate cancer-specific survival.
Limitations of this analysis include the lack of information on subsequent therapy and the inherited limitations of the TOAD trial itself (low numbers, heterogeneity).
In this interesting sub-group analysis of the TOAD trial, the authors of this study demonstrate that the overall survival benefit demonstrated in the TOAD trial may be significantly impacted by whether patients received ADT prior to trial entry. There are multiple possible explanations for this difference in addition to post-hoc trial selection bias, including issues surrounding potentiation of androgen sensitivity, with significant implications for treatment of relapsed prostate cancer and future study planning.
One question I had, which they answered, was whether prior ADT use just reflected use of primary radiotherapy – but when they limited the study to only patients who received radiation therapy (not surgery), they found similar results to their initial analysis.
Presented by: Kristian Stensland, MD, SUO and Health Services Research Fellow, University of Michigan
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 American Urological Association, AUA 2021- Virtual Meeting, Sept 10-13, 2021.
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