(UroToday.com) The 37th Annual European Association of Urology Congress held in Amsterdam, Netherlands between July 1st, and 4th 2022 was host to a session addressing controversies in urologic oncology. Professor Alberto Briganti was tasked with arguing in favor of metastasis-directed therapy in prostate cancer patients with PET-detected oligorecurrent prostate cancer.
Dr. Briganti began his presentation by discussing the impact of PSMA-PET/CT usage on changes in the management of patients with biochemical recurrence (BCR). Han et al. demonstrated that the pooled proportion of management changes following usage of this imaging modality was 54%. Use of systemic treatment decreased from 26% to 12% and a lower proportion of patients subsequently received no treatment (14% to 11%).1 Unfortunately, it is yet unknown whether this change in management after the introduction of PET PSMA is associated with improved patient outcomes.
The diagram below demonstrates the metastasis-directed therapy (MDT) management options for patients with oligorecurrent prostate cancer.
What is the consensus among the experts? A survey of the attendees from the latest APCCC meeting demonstrated that the majority of experts (67%) are in favor of MDT plus systemic therapy in patients with low volume/oligometastatic metachronous mHSPC (e.g. 3 bone lesions on next-generation imaging).
Patient selection is key for MDT. We need to consider:
- Number of metastatic sites (up to 5 permissible)
- Site of metastasis (LNs versus bone versus visceral)
- PSA level at the time of MDT
- Imaging modality used
- Volume at imaging
- Longer time to progression
Level 1 evidence supporting use of MDT potentially in patients with oligorecurrent disease is limited to 3 Phase II trials (STOMP, ORIOLE, SABR-COMET).2,3 The two trials limited to PCa patients (STOMP, ORIOLE) randomized patients to MDT (surgery or SBRT in STOMP; SBRT only in ORIOLE) versus observation and demonstrated improvements in “early’ outcomes of interest:
- Improved ADT-free survival in the STOMP trial (HR: 0.53, p<0.05)
- Improved 6 months PFS in ORIOLE (61% versus 19%)
The question becomes: are these endpoints strong enough for men with overall long median survival?
Dr. Briganti notes that we should consider the natural history of such patients, which overall is quite favorable. Data from the STOMP trial demonstrates that the ADT-free survival in the placebo arm is 12 months (21 months in the MDT arm). But instead of considering ADT-free survival as an outcome of interest, should we not intensify the treatment with both ADT and MDT in such patients?
What other lessons can we learn about MDT from these trials. Subgroup analysis from the ORIOLE trial of patients with 1-3 metastases on conventional imaging demonstrated that patients with partial ablation of the lesions (i.e. remaining untreated lesions) fared significantly worse compared to patients who had all lesions treated.
What about the association of high-risk mutation status with PFS after SABR? The ORIOLE trial demonstrated that patients without high-risk mutations (i.e. without TP53, ATM, BRCA1/2, RB1) responded much more favorably to MDT, compared to patients with high risk mutations.
There continues to be an increasing number of Phase II single-arm prospective trials evaluating MDT in patients with oligorecurrent disease. A crude summary of these heterogenous trials shows:
- At 2-3 years, roughly 20-30% of men are free from PSA recurrence/ADT
- In-field recurrences with MDR are very low
- MDT (SBRT/surgery) has limited toxicity (Grade 2: 8-15%, Grade 3: 0-2%)
One potential pitfall of MDT is in patients with PSMA-detected LN involvement. PSMA-PET/CT has poor accuracy in detection LN involvement, on a per lesion basis. Thus, patients who have 1-2 LNs appearing on PSMA-PET/CT, may actually harbor further disease in other LN sites. Thus, targeted therapy with MDT to those lesions only may represent undertreatment in that setting. This has been reflected by Fossati et al who demonstrated that 3-year complete- response-free survival was 58% in patients undergoing an extended salvage lymph node dissection (sLND) versus 41% and 40% in those receiving targeted sLND and targeted SBRT (p<0.001).
Similarly, elective nodal pelvic radiotherapy (EMRT) in patients with 1 positive node on PSMA was associated with improved new metastasis-free survival compared to those undergoing SBRT.4
But what about the increased toxicity of adding whole pelvic XRT to MDT? Results from the STORM trial (Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases), an international phase II, open-label, randomized trial of patients diagnosed with PET-detected pelvic nodal oligorecurrence (<=5 nodes) following radical local treatment for PCa. Such patients were randomized in a 1:1 fashion to:
- Arm A: MDT + 6 months of ADT
- Arm B: ENRT (25x1.8Gy) + MDT + 6 months of ADT
The primary endpoint was MFS. Results presented by Professor Ost at the EAU 22 meeting demonstrated no significant differences in Grade 2 or worse GI or GU toxicities.
But should MDT + ADT be the control arm in the STORM trial? Data from a retrospective case series of 305 patients with PSMA PET positive oligorecurrence (5 or less sites), demonstrated that the addition of ADT to MDT was associated with improved biochemical PFS.5
Results from the latest APCCC meeting, demonstrated that most panelists were in favor of:
- ADT + MDT for patients with oligorecurrent disease (67%)
- If systemic treatment is given, 68% were in favor of ADT plus an androgen receptor inhibitor (abiraterone, apalutamide or enzalutamide)
- If systemic treatment plus MDT is given for metachronous, low volume mHSPC, 68% voted for intermittent systemic therapy
Dr. Briganti concluded with the following take home messages:
- MDT is associated with low toxicity and rates of in-field recurrences
- The main endpoint is to decrease cancer progression
- Patient selection is mandatory (use PSMA PET)
- Strong Phase 3 data is yet to be published
- Combination therapy is likely the key
Presented by: Alberto Briganti, MD, PhD, Professor of Urology, Department of Urology, Università Vita-Salute San Raffaele, Milan, Italy
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @during the 2022 European Association of Urology (EAU) Annual Hybrid Meeting, Amsterdam, NL, Fri, July 1 – Mon, July 4, 2022.
References:
- Han S, et al. Impact of 68 Ga-PSMA PET on the Management of Patients with Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2018;74:179-90.
- Phillips R, et al . Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncology 2020;6:650-9.
- Palma DA, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol 2020;38:2830-8.
- De Bleser E, et al. Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-institutional Analysis Comparing the Outcome and Toxicity of Stereotactic Body Radiotherapy and Elective Nodal Radiotherapy. Eur Urol. 2019;76:732-9.
- Kroeze SG, et al. Prostate-specific Membrane Antigen Positron Emission Tomography-detected Oligorecurrent Prostate Cancer Treated with Metastases-directed Radiotherapy: Role of Addition and Duration of Androgen Deprivation. Eur Urol Focus. 2021;7:309-16.
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