(UroToday.com) The 37th Annual European Association of Urology Congress held in Amsterdam, the Netherlands between July 1st, and 4th 2022 was host to a session about the management of metastatic hormone sensitive prostate cancer (mHSPC). Dr. Christopher Sweeney addressed the significant clinical differences between synchronous and metachronous metastatic hormone sensitive prostate cancer (mHSPC).
Dr. Sweeney began his presentation by defining patients with metachronous mHSPC as those patients who typically relapse after presentation with localized disease and were managed initially by definitive therapy with prostatectomy and/or radiation or watchful waiting. As opposed to the M0CRPC patients who have rising PSA treated with ADT and subsequently develop castration resistance, metachronous mHSPC are those observed in the setting of rising PSA until metastasis develops and then have ADT started.
This distinction between metachronous and synchronous presentation is critical, as patients in these two groups have different prognoses with testosterone suppression alone. Historical data (now outdated with advances in the management of metastatic prostate cancer) from CHAARTED and GETUG15 demonstrate the following median overall survivals for patients treated with testosterone suppression alone:1
- Metachronous and low volume: ~8 years
- Metachronous and high volume: 4.5 years
- Synchronous and low volume: 4.5 years
- Synchronous and high volume: 3 years
*High volume: visceral metastases and/or 4 or more bone metastases with at least one beyond the vertebral column and pelvis
Data from the Dana-Farber Cancer Institute demonstrated that:
- 56% of low volume mHSPC cases are metachronous in nature
- ~15% of all patients relapse after RP/XRT with high volume disease
But how do we reach this metachronous mHSPC disease state? Should patients with evidence of biochemical relapse historically not receive ADT and develop metastasis only following castration resistance? Not necessarily. Dr. Sweeney referenced data from Makarov et al. published in The Journal of Urology in 2008. 3,096 patients underwent a radical prostatectomy at Johns Hopkins University. Of these 3,096 patients, 422 developed biochemical recurrence (PSA >0.2 ng/dL) and were managed with surveillance until time of metastasis. Of these 422 patients with biochemical recurrence, 91 developed metastatic disease and 41 died of prostate cancer (50 of non-prostate cancer related causes). When looking at the figure below, the median time between PSA failure and development of metastasis was 32 months, meaning hormonal therapy was spared for 32 months. Median time from metastasis to prostate cancer mortality was 82 months. Looking at this from a broader perspective, the median time from PSA failure to death was 132 months, and time from radical prostatectomy 168 months.2
Given these findings, Dr. Sweeney argued that yes in fact it is “good medical care to survey patients with biochemical relapse with periodic conventional imaging and defer ADT until metachronous mHSPC”.
Dr. Sweeney emphasized that patients with mHSPC can be quite dissimilar and that there are “extreme faces” of mHSPC:
- One extreme: 55-year-old with no comorbidities and high volume de novo/synchronous metastatic disease
- Other extreme: 82-year-old with congestive heart failure and coronary artery disease with 2 bone metastases 10 years after prostatectomy
Different treatment paradigms
Eight-year overall survival CHAARTED data recently presented by Tripathi et al. at ASCO 2022 demonstrates that docetaxel added to testosterone suppression shows:
-Clear overall survival benefit:
- Synchronous high volume
- Metachronous high volume (smaller sample size)
-Modest effect: Synchronous low volume disease
-No meaningful effect:
- Metachronous low volume disease
- Biochemical relapse
- Adjuvantly
Thus, one can deduce that both volume and timing of metastatic disease are prognostic and predictive for docetaxel benefit.
The same does not hold true for treatment with second generation anti-androgens. Davis et.al recently presented updated overall survival data from ENZAMET at ASCO 22 and demonstrated that enzalutamide added to testosterone suppression improves PFS and OS across all four subgroups. This is similar to findings seen with ARCHES, TITAN, LATITUDE, STAMPEDE-abiraterone.
Interestingly, subgroup analysis from this trial, which permitted docetaxel use, clearly demonstrates that docetaxel addition to enzalutamide + testosterone suppression only shows a survival benefit in the poorest prognosis group (i.e synchronous, high volume). These findings are similar to those seen with PEACE-1 and ARASENS.
Dr. Sweeney next addressed whether the biology drives the clinical phenotypes associated with metachronous versus synchronous HSPC.
Data from the GAP6 Movember initiative clearly demonstrates increasing mutation frequency with increasing volume and synchronous metastasis, specifically with regards to TP53 (p=0.01), WNT (p=0.04), and Cell Cycle genes (p=0.004).
Accordingly, can the biology add to/replace clinical variables for prognosis and treatment selection? It appears so. Hamid et al. published in 2019 results from the Dana-Farber mHSPC cohort and demonstrated that patients without p53, RB1, or PTEN mutations had much longer overall survival rates.3
Data from the Johns Hopkins University cohort by Sutera et al. published in 2022 demonstrated as well that patients without p53 mutations and oligometastatic disease (light grey line below) had the best rPFS rates.4
Dr. Sweeney concluded with his proposed mHSPC treatment plans:
Presented by: Dr. Christopher Sweeney, MBBS, Professor, Medical Oncology, Department of Medicine, Dana-Farber Cancer Institute, Boston, MA
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2022 European Association of Urology (EAU) Annual Hybrid Meeting, Amsterdam, NL, Fri, July 1 – Mon, July 4, 2022.
References:
- Francini E, et al. Time of metastatic disease presentation and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC). Prostate. 2018;78(12):889-95.
- Makarov DV, et al. The natural history of men treated with deferred androgen deprivation therapy in whom metastatic prostate cancer developed following radical prostatectomy. J Urol. 2008;179(1):156-61.
- Hamid AA, et al. Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer. Eur Urol. 2019;76(1):89-97.
- Sutera P, et al. Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics/ Prostate Cancer Prostatic Dis. 2022.