(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). Professor Noel W. Clarke was tasked with arguing in favor of targeted therapy for both the primary disease and metastatic sites in the management of de novo metastatic hormone sensitive prostate cancer (mHSPC) patients with oligometastatic disease (cT3N+M1a).
Professor Clarke began his presentation by shedding light on the definitions of “metastasis” and “oligo”. Although such terms have clear definitions per Wikipedia and the Oxford English Dictionary, the definition of oligometastatic disease in the prostate cancer disease space remains controversial. A report from the Advanced Prostate Cancer Consensus Conference (APCCC) 2017 showed significant variability in the experts’ definition of “oligometastatic prostate cancer that influences treatment decisions (local treatment of all lesions +/- systemic therapy)”:
Professor Clarke notes that given a lack of consensus on the definition of oligometastatic disease, how can one even reach a consensus on the appropriate management of such patients?
It is clear that not all oligometastatic patients have the same prognosis. In addition to volume of the metastatic burden, it is important to consider the location of disease spread. Using a SEER cohort analysis, Ali et al. evaluated the importance of non-regional lymph nodes in assigning risk in primary metastatic prostate cancer. Patients with non-regional LN involvement and bone lesions had significantly worse all-cause (HR: 1.16, 95% CI: 1.08 – 1.24) and prostate cancer-specific mortalities (HR: 1.15, 95% CI: 1.07 – 1.24) compared to patients with only bone metastases. The authors of this study concluded that: “The current therapeutic stratification of 'low-' vs 'high-volume' disease does not account for this phenomenon, and patients requiring aggressive combination therapy may not receive maximum therapeutic benefit as a consequence.”1
Going back to the patient initially presented by Dr. Heidegger with de novo mHSPC (low risk/low volume) with cT3N+M1a disease, it remains difficult to choose the appropriate treatment for this patient within the context of previous clinical trials in this disease space:
- CHAARTED 2015: This patient would likely be considered low volume due to the absence of bone metastases, however lymph node presence/burden was not considered/reported in this trial
- LATITUDE 2017: This patient does not have two of the three high-risk prognostic factors (Gleason Score 8 or worse disease, presence of 3 or more lesions on bone scan, presence of measurable visceral metastasis)
- STAMPEDE Arm G: 2017: No burden/risk stratification
- STAMPEDE Arm H (M1RT) 2018: Low disease burden
When considering treatment options for this patient, one must consider if the treatment of choice has shown efficacy in the corresponding patient population. In 2019, Professor Clarke’s group performed a post hoc subgroup analysis of the 2017 STAMPEDE trial evaluating abiraterone combination with ADT in patients with mHSPC, stratified by the LATITUDE risk and CHAARTED disease volume criteria. The table below demonstrates the breakdown of the 901 STAMPEDE patients:
Despite initial concerns that abiraterone may only be of benefit in LATITUDE “high-risk” patients, this analysis demonstrated that abiraterone maintained consistent overall, failure-free, progression-free, and prostate cancer-specific mortality benefits across the LATITUDE and CHAARTED risk group classifications.2
The question next addressed by Professor Clarke is whether the primary site should be treated in M1a disease. Recent data from the STAMPEDE Arm H, with median follow up of 61.3 months, demonstrates that additional of radiation therapy to standard of care treatment significantly improves overall survival in patients with low, but not high, metastatic burden (HR: 0.64, 95% CI: 0.52 – 0.79).3
The next question becomes: what is the metastatic burden cutoff when offering radiation therapy to these patients? Professor Clarke’s group again performed a post hoc analysis of 1,939 STAMPEDE patients. Survival benefit decreased continuously as the number of bone metastases increased, with the benefit most pronounced up to 3 bone lesions, after which no significant benefit was appreciated. Further analysis based on subgroups showed that the magnitude of benefit from the addition of prostate radiotherapy was greater in patients with low metastatic burden with only nonregional lymph nodes (M1a) or 3 or fewer bone metastases without visceral metastasis (HR for OS, 0.62; 95% CI, 0.46-0.83; HR for FFS, 0.57; 95% CI, 0.47-0.70) than among patients with 4 or more bone metastases or any visceral/other metastasis (HR for OS, 1.08; 95% CI, 0.91-1.28; interaction P = .003; HR for FFS, 0.87; 95% CI, 0.76-0.99; interaction P = .002).4
What about metastasis-directed therapy in patients with oligometastatic disease? Ost el. Performed a multi-institutional cohort analysis of 119 patients from 7 international centers with mHSPC with 1-3 sites of metastatic disease. Half of these patients received a short course of hormone therapy (median duration 2 months) and were followed for a median of 3 years (IQR: 1.8 – 4.0). As demonstrated below, the median distant PFS was 21 months (95% CI: 15- 26 months). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr lesion PFS of 79% for patients treated with a biologically effective dose ≤100Gy versus 99% for patients treated with >100Gy (p=0.01). This study however is limited by its single arm nature with no comparator group and short follow-up period.5
Given the lack of current high quality evidence supporting metastasis directed therapy, one would expect this treatment approach to be met with skepticism by the urologic oncology community. However, a survey of the 2022 APCCC attendees queried the audience regarding the recommended treatment modality for patients with clinically localized prostate cancer but 1-3 PSMA PET positive bone lesions? Half of the responders chose “Treat as M0 plus Metastasis Direct Therapy”, which was of great surprise to Professor Clarke given the lack of high-quality evidence supporting this approach.
Professor Clarke notes that we await the results of STAMPEDE 2, that will evaluate SABR in low volume metastatic disease (defined as up to 5 metastases on standard imaging)
Professor Clarke concluded by circling back to the original question: “Is targeted therapy of the primary and metastases the way to go?”
Answer: To the primary site and pelvis, but not without systemic therapy as well.
Presented by: Professor Noel W. Clarke, MBBS, FRCS, ChM, Department of Urology, Christie Hospital, Manchester, UK
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:
- Ali A, et al. Importance of non-regional lymph nodes in assigning risk in primary metastatic prostate cancer. BJU Int. 2019;123(1):65-73.
- Hoyle AP, et al. Abiraterone in "High-" and "Low-risk" Metastatic Hormone-sensitive Prostate Cancer. Eur Urol. 2019;76(6):719-28.
- Parker CC, et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Swtzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Med. 2022;19(6):e1003998.
- Ali A, et al. Association of Bone Metastatic Burden With Survival Benefit From Prostate Radiotherapy in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2021;7(4):555-563.
- Ost P, et al. Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis. Eur Urol. 2016;69(1):9-12.