SIU Virtual Congress 2020: Debate: Management of the Metastases in Oligometastatic Prostate Cancer - The Metastases Should be Treated with Metastasis-Directed Therapy

As such, Dr. Cheung notes that his formal position on this topic is that these patients should all be enrolled into a randomized clinical trial, given that he believes there is clinical equipoise between systemic therapy alone versus systemic therapy plus metastasis-directed therapy for oligometastatic hormone-sensitive prostate cancer.

Oligometastases were first described in 1995 as a disease state between locoregionally confined and widely metastatic where there are limited metastases in number and location. This can occur de novo, or can be induced from a widely metastatic state from effected systemic therapy. The most common definitions for oligometastatic disease are ≤3 metastases and ≤5 metastases. The conventional goal of surgery for oligometastases is that there may be a chance for a cure, however, the more modern goal is that there is a delay to progression and maybe an improvement in overall survival. Metastasis-directed therapy for oligometastatic disease includes surgery, stereotactic body radiotherapy, and radiofrequency ablation as the most common modalities. The goal of metastasis-directed therapy is to eradicate the visible tumors, or at the least to provide some long-term local control. Surgery has historically been the gold standard but stereotactic body radiotherapy/radiofrequency ablation can be an alternative or complementary to surgical resection, particularly:

• For patients who are medically inoperable or elderly
• For tumors which require technically difficult or morbid surgery (small or deep lung tumors not amenable to wedge resection, bone/spine mets, etc.)
• When it can be combined with surgery to treat multiple tumors in various sites
• When it can be easily integrated with systemic therapy

Until recently, there has been very little data supporting non-cranial stereotactic body radiotherapy as metastasis-directed therapy. However, in 2019 the SABR-COMET study was published in The Lancet.¹ This randomized, open-label Phase II study was done at 10 hospitals in Canada, the Netherlands, Scotland, and Australia that randomized 99 patients (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus stereotactic body radiotherapy to all metastatic lesions (SABR group). Over a median follow-up was 25 months (IQR 19-54) in the control group versus 26 months (23-37) in the SABR group, median overall survival was 28 months (95% confidence interval [CI] 19-33) in the control group versus 41 months (26-not reached) in the SABR group (hazard ratio [HR] 0.57, 95% CI 0.30-1.10; p=0.090). Recently published long-term outcomes of this trial showed durable findings.² Over a median follow-up of 51 months, the 5-year overall survival (OS) rate was 17.7% in the control group (95% CI 6% to 34%) versus 42.3% in SABR group (95% CI 28% to 56%; stratified log-rank p = 0.006), and the 5-year progression-free survival (PFS) rate was not reached in the control group (3.2%; 95% CI 0% to 14% at 4 years with last patient censored) and 17.3% in the SABR group (95% CI 8% to 30%; p = 0.001):

Dr. Cheung suggests that for oligometastatic prostate cancer we need to distinguish between hormone-sensitive versus castration-resistant disease, as well as take into consideration synchronous versus metachronous presentation and conventional versus novel PET imaging. In his opinion, there are two main strategies: (i) using metastasis directed therapy alone (to delay need to start systemic therapy), and (ii) use of metastasis directed therapy with systemic therapy.

There have been two Phase II trials assessing metastasis-directed therapy for oligometastatic prostate cancer. In the STOMP trial, Ost and colleagues randomly assigned 62 patients to either surveillance or metastasis-directed therapy of all detected lesions (surgery or stereotactic body radiotherapy), with a primary end point of androgen deprivation therapy (ADT)-free survival. At a median follow-up time of 3 years (IQR 2.3-3.75 years), the median ADT-free survival was 13 months (80% CI 12 to 17 months) for the surveillance group and 21 months (80% CI 14 to 29 months) for the metastasis-directed therapy group (HR 0.60, 80% CI 0.40 to 0.90; log-rank p = 0.11):




The second Phase II trial published recently was the ORIOLE trial,⁴ randomizing 54 men in a 2:1 ratio to receive stereotactic body radiotherapy or observation. The primary endpoint for this trial was progression at 6 months, defined as a prostate-specific antigen (PSA) increase, radiographic or symptomatic progression, ADT initiation, or death. Progression at 6 months occurred in 7 of 36 patients (19%) receiving stereotactic body radiotherapy and 11 of 18 patients (61%) undergoing observation (p = 0.005). Furthermore, treatment with stereotactic body radiotherapy improved media PFS (not reached v.s 5.8 months; HR 0.30, 95% CI 0.11-0.81; p = 0.002):

For those patients in the stereotactic body radiotherapy arm that had a prostate-specific membrane antigen (PSMA) PET-CT scan, the proportion of men with disease progression at 6 months was 5% in those who did not have any untreated lesions, compared to 38% in those who did have some untreated PSMA avid lesions (p=0.03).

Dr. Cheung concluded his presentation with the following summary remarks:

• The SABR-COMET trial gives a strong signal that stereotactic body radiotherapy can improve PFS and OS in metachronous oligometastatic prostate cancer
• Two small published randomized Phase II studies in oligometastatic hormone-sensitive prostate cancer revealed that surgery/stereotactic body radiotherapy for metachronous metastases can delay progression and the need to start ADT (if one considers surveillance to be an acceptable option to compare against)
• Starting ADT can be considered a surrogate of development of polymetastatic disease in the STOMP trial, and surgery/stereotactic body radiotherapy delayed start of ADT
• There is no randomized data evaluating the use of metastasis-directed therapy in the setting of synchronous (de novo) hormone-sensitive oligometastatic prostate cancer
• There is no randomized data evaluating the use of metastasis-directed therapy in combination with standard (or any) systemic therapy in the setting of hormone-sensitive oligometastatic prostate cancer
• Stereotactic body radiotherapy is very well tolerated for the most part and it is likely best used in combination with systemic therapy for hormone-sensitive oligometastatic prostate cancer