My study at ASCO GU was mainly about our secondary analysis of the SWOG 1216 phase III trial and the impact of time of metastasis after prostatectomy on survival outcomes in metachronous metastatic hormone sensitive prostate cancer.
So, a little background before I talk about my study. We know that metastatic hormone sensitive prostate cancer presents in two distinct forms: first de novo and metachronous. De novo mHSPC, which means that there are metastases at the time of diagnosis, tends to be more aggressive with a higher tumour burden and lower response rate to ADT plus or minus intensification. Some studies suggest that de novo metastatic cancers arise from more aggressive tumour clones and more key driver mutations. However, in the case of metachronous mHSPC, where metastases develop after initial localised treatment, the prognostic significance of time to metastasis remains unclear. Similar trends in other cancers such as breast, colorectal and RCC indicate that late recurrence post-surgery may correspond to a more indolent disease course and improved overall survival. So this gap in knowledge led us to further investigate the role of time to metastasis in mHSPC.
What was the study design?
We mainly used the database related to the SWOG 1216 trial. The SWOG 1216 trial evaluated the efficacy of androgen deprivation therapy plus orteronel, which is a cytochrome 17A inhibitor with a structure similar to abiraterone, versus ADT plus bicalutamide in patients with mHSPC. However, our analysis specifically focuses on metachronous mHSPC patients who had previously undergone radical prostatectomy. By examining this subgroup we aimed to determine whether time to metastasis impacts survival outcomes. If TTM serves as a prognostic factor it could refine the existing predictive models and potentially guide treatment decisions, helping clinicians stratify patients based on recurrence timing.
So, our primary objective was to evaluate whether TTM is predictive of survival outcomes in patients with metachronous mHSPC. The secondary objectives of the study included assessing progression free survival and overall survival across different TTM thresholds. Additionally, we aimed to investigate whether TTM influences treatment response in patients receiving ADT plus an ARPI versus ADT plus bicalutamide. For this analysis we defined metachronous mHSPC as having the absence of metastatic disease within 90 days of the initial diagnosis and time to metastasis was measured from the date of prostatectomy to the first metastatic diagnosis and is analysed both as a continuous variable and in pre-defined categories ranging from less than one year to more than four years.
The primary endpoints for the study included PFS and OS and we employed a Cox proportional hazards model to evaluate survival outcomes.
What were the results of this study?
Out of the 1,279 participants in the SWOG 1216 trial, 301 patients met the inclusion criteria of having undergone prostatectomy and having metachronous mHSPC. Among these, 161 patients were in the experimental arm and 150 were in the control arm. Overall 38% of the patients had extensive burden of disease and baseline characteristics were balanced between both arms.
Our results show that TTM when analysed as a continuous variable was not significantly associated with either progression free survival or overall survival, with hazard ratios nearing 1.0 in both cases. Similarly, when categorised into predefined time intervals, TTM did not appear to influence progression free survival. Results were also comparable for overall survival where no statistically significant association was seen.
So these findings remain consistent also across subgroup analyses, regardless of whether patients were treated with ADT plus orteronel or ADT plus bicalutamide. Following those intriguing results that were unexpected, we decided to validate them in our own real-world cohort at the Huntsman Cancer Institute where we included 186 patients with mHSPC who underwent radical prostatectomy and were treated with ADT plus an approved ARPI, including abiraterone, enzalutamide and apalutamide. The results were concordant with those from both the SWOG 1216 dataset, both on univariant and multivariant analysis.
What is the clinical significance of these results?
Before I go into the clinical significance I do want to try to talk about a rationale behind those results. One possible explanation for our findings is that when metastasis occurs more aggressive clones tend to dominate, especially those with key genomic alterations such as AR amplifications, TP53 mutations and PTEN loss. These alterations drive treatment resistance in general and disease progression which may neutralise any advantage of delayed metastasis.
A good consideration to have is that ADT and ARPIs currently are highly effective in controlling metastatic disease, regardless of when the metastases occur.
So, based on our findings, time to metastasis should not be used as a prognostic marker to guide treatment decisions in patients with metachronous mHSPC. Regardless of whether metastases occur early or late, these patients should be managed with treatment intensification strategies such as ADT plus ARPIs. Rather than relying on TTM, clinicians should focus on more meaningful stratification factors such as disease burden and molecular profiling to help them with treatment decisions.
What is next for this study?
Our next step for this study is to do a more granular analysis of those patients that recur after a very long time, let’s say more than ten years after surgery and see if they have any specific characteristics, either clinical or genomic characteristics. Thank you.
