When the PSA is elevated following initial potentially curative treatment with prostatectomy or radiation therapy, the customary management response has been hormone suppression with Lupron, Degarilix or Relugolix. This Commentary highlights an alternative three-pronged approach for selected men that prolongs metastasis-free survival and androgen deprivation-free survival as compared to hormone suppression monotherapy.
The First Element: The 68Ga-PSMA-11 or Pylarify PET/CT scans have the sensitivity to detect low-volume recurrence at PSA values of less than 0.5 ng/mL. These metabolic scans, significantly superior in sensitivity to conventional CT and technetium bone scans, detect PSMA biomarked lesions as small as 4 millimeters in size.
Overall detection rates by the two PSMA PET scans were positive in ~50% of men with recurrence in the PSA range of <0.5 ng/mL. and between 72 and 89% the range of less than 1.0 ng/mL.
- Pylarify detection rate was studied by Mena et al., NCI Molecular Imaging Program(J. Nucl Med 2020) in 90 men who were negative on conventional imaging and noton ADT. Their findings: Pylarify was positive in 47.6%, 50%, 89% and 94% at PSAlevels of >0.2 to <0.5; 0.5 to <1.0; 1.0 – <2.0 and >2.0 ng/mL.
- 68Ga-PSMA -11 detection rate was studied in 2533 men by Oronicg et al., (EuroNuc Med & Mol Imaging, 2021). Their findings: PSMA PET was positive at PSAvalues <=0.2 in 45%; in 58% at 0.2 – <=0.5; and in 72% between PSA values of>0.5 and <=1.0 ng/mL.
A panel of specialists cited by Rogowski concluded, “A PSAthreshold of0.3 to 0.83 ng/ml appears to be an optimal cut-off value for using PSMA PET/CT as staging” Rogowski et al., Rad Oncol. 2021,”Radiotherapy of oligometastatic prostate cancer: a systematic review.” They found that in the majority of cases only one or two lesions were found, located in bone or lymph nodes.
The PSMA PET can also be informative in men with recurrent disease during ADT. Fassbind et al., found positive scans in 85.2% of men receiving hormone suppression with PSA values between 0 – 1.0 ng/mL. (Annals Nuc Med, 2021).
The Second Element: The identification of three or fewer lesions (in some cases up to five) fulfills the current definition of oligometastatic disease and sets the stage for metastasis directed therapy (MDT) with Stereotactic Body Radiation Therapy (SBRT). The panel of experts cited by Rogowski “recommended PSMA PET/CT to confirm the diagnosis of an oligometastatic disease after radical treatment.”
The recommendation for PSMA PET staging was clearly supported by the findings in the ORACLE trial (Ost et al., JCO. 2017). This trial randomized 54 men with one to three recurrent metastases lesions up to 5 cm in size to either SBRT or observation for 6 months. ADT was not used. By 6 months 19% of men in the SBRT arm had progressed compared to 61% who received no treatment. Those men treated on the basis of CT and bone scans experienced a progression-free survival of 13 months. Of significance however, a subcategory of men who were treated on the basis of baseline PSMA findings experienced a PFS of 33 months— emphasizing the importance of treating all identifiable lesions, i.e., treating the lesions not seen on the CT and bone scans.
The Third Element: The outcome of MDT in men with castration resistant oligometastatic disease.
Most men will encounter the option of MDT after they progress during hormone suppression, become castration resistant and then diagnosed on a sensitive PET/CT with a low burden of metastatic disease— an increasingly common situation. Brennan et al., (Adv Rad Oncol 2020) reported retrospectively the PFS and PSA response to MDT in 35 men, 28 having progressed on hormone suppression (and other therapies). Twenty four of 35 had 1 -2 metastatic lesions and 13 had 3-5. A PSA decline of > 50% occurred in 63% of men. In the 22 men who had complete ablation of PSMA PET visualized lesions the median PFS was 13 months; overall survival was 95% at one year. All men had bone metastases [the most common site of prostate cancer metastases].
Although not comparable, the authors cited PFS in two trials for systemic therapies in generally similar groups of men with metastatic CRPC progressing after second line hormone therapy; the PFSs were 5.7 and 7.9 months.
Research on the effectiveness of MDT is extensive. What has been learned to date?
- The preferred diagnostic technique is either a PSMA PET/CT with the 68Ga-PSMA-11or the Pylarify scans.
- Local control of metastatic lesions with SBRT is >90% at 2-year follow-up, and becauseof low toxicity retreatment is possible.
- MDT of low-burden metastases prolongs progression-free survival with or without ADT, while its effect on overall survival is currently undetermined awaiting the results of trials.
- 75% of members of an expert panel would accompany MDT with hormone suppression, although its avoidance spares toxicity — an appropriate discussion for a patient and his oncologist.
- The ORACLE trial found that MDT boosts immunologic sensitivity to micrometastatic lesions and may be an important element in its effectiveness.
- A protocol is studying combination therapy of Rad-223 (Xofigo) and MDT.
The Missing Link: Wanted: A validated gene expression profile defining a ‘true’ oligometastatic state.
The concept of an oligometastatic state was first proposed in 1995 as an intermediate state — metastatic, yes, but less biologically aggressive with limited potential for additional dissemination. Currently men are selected for MDT on features such as number, size and location of metastatic sites, a low initial PSA and Gleason Score and late metastatic presentation after primary treatment. However, a molecular characterization has escaped definition — but not for lack of effort. The ongoing search for identifying biomarkers has focused on serum micoRNAs, next generation sequencing of circulating tumor cells, circulating tumor DNA and extracellular vesicles (exosomes). Until (and if) a molecular profile is validated, oligometastatic prostate cancer will remain a heterogeneous entity with variable prognoses.
With the increasing availability of the newer and more sensitive PET/CT scans, a low burden of ‘oligometastatic’ prostate cancer is being found more frequently, providing the option of metastasis directed therapy.