PCa Commentary | Volume 182 – October 2023

Posted by Edward Weber | October 2023

Oligometastatic Prostate Cancer: Metastasis Directed Therapy (MDT) – Treatment Options

Background

With the increased use of PSMA PET/CT scanning both at initial diagnosis of advanced prostate cancer and at disease recurrence, a substantial number of men will be found to have some extent of metastatic disease — either metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC). The second of these states will have arisen in what is termed ‘non-metastatic’ castration-resistant cancer (rising PSA despite castrate level of testosterone), in which, upon PET scanning, metastases are frequently identified. There is no current consensus regarding the appropriate treatment regimens for these disease states. Three options have been studied:

• Metastases-directed radiation therapy only, i.e., no androgen deprivation therapy (ADT)
  until progression
• MDT combined with ADT
• The newest option, MDT combined with intermittent hormone therapy (IHT)

Studies to date report that all three options prolong overall survival compared to ADT only.

Dividing mHSPC into High Tumor Burden vs Low Tumor Burden

Two major clinical trials (STAMPEDE and CHAARTED) have defined ‘high burden’ as: the presence of visceral metastases or four or more bone lesions one or more beyond the vertebral bodies and pelvis. These studies were based on standard CT and bone scans. This distinction between high and low burden disease has been developed to guide therapeutic regimens such as systemic treatment with Docetaxel with ADT +/- newer anti-androgen receptor agents i.e., Zytiga  or Xtandi) for high-burden disease. For low burden disease, MDT+/- ADT are options, including ablation of the prostate.

An early trial reported by Palma et al, Lancet 2019, established that MDT alone for men with 1-5
metastases had a superior overall survival than ADT only (SABR-COMET trial). Currently recruiting is NCT03721341 using MDT for treatment of 4-10 oligometastatic lesions combined with a variety of standard of care options as selected by the treating physician vs any chosen treatment option but without MDT.

Currently recent and ongoing studies in low burden disease focus on avoiding ADT until disease progression thus avoiding ADT toxicity.

New Techniques Under Development for Estimating Prognosis

Patient selection for MDT is currently best made with PSMA PET/CT scanning, which offers greater sensitivity than conventional imaging. Research is developing techniques to predict prognosis with greater sensitivity. One promising option is assessing the metabolic aggressiveness of the metastatic lesions under consideration for MDT by measuring the  PET SUV (specific uptake value) of individual lesions. SUV is a measure of cancer aggressiveness. In this assessment the SUVmax is calculated, which totals the combined metabolic activity of all the lesions. This requires special technology.

However, the mHSPC disease state is a heterogeneous collection of members each with different
biological behavior and a different risk of progression. An estimate of prognoses for a man with
mHSPC can be assessed by applying the genomic classifier Decipher on tissue from the primary.
A more technologically advanced assessment of biological behavior would be evaluating
microRNA or circulating tumor DNA in blood.

Initial Studies: The ORIOLE and STOMP trials of MDT 

The above-named studies were two early randomized trials of mHSPC employed MDT (with stereotactic radiation therapy) versus observation only in men with 3 or fewer metastatic sites.

The outcome of both trials (as reviewed by Deek et al., JCO 2022), was a prolongation of progression-free survival (PFS) in both studies. MDT targeted three or fewer lesions based on CT and bone scans in each man in the MDT arm. Progression-free survival was superior in both trials compared to observation only with a pooled median PFS of 11.9 months in the MDT arms and 5.9 months with observation only. Men in the study with high-risk mutations in the genes BRCA 1/2, ATM. RB1 and TP53 who received MDT also benefited, but to a lesser extent with a median PFS of 7.5 months.

In the ORIOLE trial at onset, in addition to CT and bone scans, men also had PSMA PET scans. The PET scans detected a total of 36 lesions of which 16 had not been seen on the CT and bone scans, emphasizing the importance of basing MDT on imaging with PSMA PET/CT.

The EXTEND Trial (NCT03599765)

The question addressed in “Addition of Metastases-Directed Therapy to Intermittent
Hormone Therapy for Oligometastatic Prostate Cancer,” Tang et al., JAMA Oncol. 2023, was “Does the addition of metastasis-directed therapy to intermittent hormone therapy improve progression-free survival for men with oligometastatic prostate cancer?” The study anticipated that the known “synergy” between hormone therapy and radiation therapy, would benefit the MDT treated group. MDT was delivered with the CyberKnife to 5 or fewer lesions. The study was randomized 1:1 between those receiving MDT therapy plus IHT and those receiving IHT only. The participants were stratified by the number of metastatic lesions (1-2 vs 3-5). All men received radiation to the prostate. Although some had received varying periods of HT pre-study, at trial onset androgen suppression was delivered for 6 months, after which hormone therapy was withheld until progression. Progression was defined as clinical or a PSA rise of greater than 25% or greater than 2 ng/mL above the nadir.

Both the ORIOLE and EXTEND trials found evidence that the immune system was sensitized to
attack metastatic sites that were too small to be imaged. The presumed explanation: In
destroying the targeted lesions intracellular proteins were released that sensitized T-cells to
attack additional metastatic site too small to be imaged.

Results

At the time of the report’s analysis the median PFS had not been reached in the MDT /IHT arm but was 15.8 months in the IHT-only group.

A secondary goal of the trial was to prolong the duration during which the testosterone level was near normal. After stopping  ADT at 6 months the men in IHT group experienced testosterone levels greater than 150 ng/dL (low normal) for only 6 months before disease progression. In the MDT/IHT arm the median duration of having a testosterone level about 150 ng/dL had not been determined at the time of data analysis.

The trial reached its goal: By adding MDT to intermittent androgen suppression PFS was prolonged and the duration of normal testosterone level before progression was extended compared to intermittent hormone therapy only.

BOTTOM LINE

The increased use of PSMA scanning at the time of diagnosis is associated with an increased prevalence of metastatic hormone sensitive prostate cancer. A variety of treatment regimens using metastasis directed therapy (MDT) are under active study.

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