There have been several historical mHSPC prognostic groups that Dr. Sweeney summarized:
- SWOG (1990s): visceral metastases and/or any lesions beyond pelvic and vertebral bones (including ie. isolated rib metastases); median overall survival with testosterone suppression +/- NSAA: 27.5 versus 51 months
- MD Anderson Cancer Center (1996): visceral metastases and/or three or more bone metastases (some vertebral degenerative joint disease possibly called metastases); median overall survival with testosterone suppression: 37.2 versus 94 months
- CHAARTED (2004): >= 4 bone metastases with one beyond pelvic/vertebral body bones and/or visceral metastases (minimize misclassification of vertebral degenerative joint disease as metastatic disease); median overall survival with testosterone suppression +/- NSAA: 34.4 versus >60 months
Additionally, there have been more recent prognostic groups for mHSPC:
- LATITUDE (2014): “high risk” definition only applied to a study of de novo metastatic disease; 2 of 3: Gleason score >=8, >=3 bone lesions, and/or presence of measurable visceral metastasis
- STAMPEDE (2021): overall survival benefit with prostate radiation in de novo mHSPC with clear benefit in <=3 bone metastases
- SWOG 9025: “disease volume was a better fit to survival data than risk group”; in high-risk: HR 1.89 (95% CI 1.29-2.80) versus high-volume: HR 2.75 (95% CI 1.84-4.10)
- CHAARTED Analysis: volume and de novo were the strongest predictors in a multivariable model, and Gleason was the weakest predictor and not available for many patients
Looking at CHAARTED and GETUG-15 data, mHSPC can be stratified by metachronous vs de novo and low vs high-volume with differences noted in overall survival:
Dr. Sweeney notes that there are extreme “faces” of mHSPC at varying points on the survival spectrum. For instance, one extreme is the 55-year-old with no comorbidities and high volume de novo metastatic disease and another extreme is the 82-year-old with CHF and CAD plus 2 bone metastases 10 years after radical prostatectomy. Indeed, these have vastly different treatment paradigms.
So, why do we develop clinical prognostic models? For docetaxel, there is some evidence of “predictive” models:
On the contrary, for androgen receptor-targeted treatment, there is no evidence of “predictive” models:
Recently, there is an emerging biological understanding of the disease with increasing mutation frequency with increasing “aggressiveness”. In a retrospective study of men with mHSPC who underwent sequencing of their tumors, the frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mHSPC spectrum1. TP53 mutation was associated with shorter radiographic PFS (26.7 versus 48.6 months; p = 0.002), and time to CRPC (95.6 versus 155.8 months; p = 0.02) in men with oligometastasis. Dr. Sweeney summarized our emerging biological understanding and treatment impact as follows:
To summarize his presentation, Dr. Sweeney concluded by again addressing if there is evidence to support the aforementioned hypotheses that men with mHSPC have a wide array of prognoses:
- That can be easily defined by clinical variables yes, the next step is to refine definitions and incorporate PSMA PET imaging
- Impacts the efficacy of different treatment strategies yes, the next step is to collate all data as part of STOPCaP individual patient data
- Have broadly distinct underlying biological profiles yes, the next step is to harmonize biological analyses from all mHSPC trials
Presented by: Christopher Sweeney, MBBS, Dana Farber Cancer Center, Boston, MA
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 the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.
- Deek MP, van der Eecken K, Phillips R, et al. The mutational landscape of metastatic castration-sensitive prostate cancer: The Spectrum Theory Revisited. Eur Urol 2021 Jan 5;S0302-2838(20)31026-5.