PCa Commentary | Volume 120 – March 2018

Posted by Edward Weber | March 2018

METASTASIS DIRECTED THERAPY:
What Can Be Learned From The First Reported Prospective, Randomized, Multicenter Phase II Clinical Trial?

In December 2017, the JCO published the trial results of Ost and colleagues: “Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence.”1 Up to this time, there have been numerous retrospective and observational studies of varying design which, taken together, strongly suggest that progression-free survival can be prolonged by the focal treatment of three or fewer lesions at the time of PSA recurrence after primary therapy. This regimen is now termed “metastasis-directed therapy” (MDT) and was discussed in detail in an earlier Commentary.

PCa Commentary #113: OLIGOMETASTATIC PROSTATE CANCER — METASTASES DIRECTED THERAPY

The potential benefit of MDT has intuitive appeal and engenders considerable hope. The regimen is premised on the possibility of a biologic “middle ground” between cancers that can be treated successfully with local therapy contrasted by biologically aggressive cancer destined to metastasize.

This as yet unproven theory postulates that there may exist a third subset of prostate cancer that is relatively indolent, having limited tendency to metastasize. It is hoped that this category of disease can be successfully cured, or substantially controlled, with focal therapy.

A further appeal of MDT is the postponement of androgen deprivation with its well-known adverse effects. On the basis of this intuition, physicians have already been conducting MDT, while at the same time acknowledging the lack of solid supporting clinical data. 

What are the Details in the Ost Trial?

The study was a small trial of 62 patients: 31 randomized to surveillance [i.e. no treatment until progression], and 31 in whom 1 to 3 asymptomatic lesions were treated focally, predominantly with focal radiation.

• Biochemical recurrence after primary therapy was determined by the standard metrics for surgery and radiation.
• On the basis of a choline PET/CT, the men with three or fewer lesions were selected. If the PET/CT was negative at the level of the prostate, a negative MRI or negative biopsy of the prostate (bed) was required.
• “Patients were stratified at random assignments by PSA doubling time (< 3 v >3 months) and location of metastases (nodal v non-nodal).”1 Testosterone had to be above 50 ng/mL. 
• PSA was checked at 3 month intervals. Re-imaging was performed if the PSA rose above a preset level or there was clinical progression. 
• ADT was also “started at symptomatic progression, progression to more than three [new] metastases, or local progression of known metastases.”1
• If at re-imaging there were three or fewer new metastases, re-treatment was allowed. 
• Because of the small size of the study it was not possible to ensure that both arms had fully comparable characteristics but, in fact, the MDT group had a bit more aggressive cancer.

What Were the Characteristics of the Patients at Biochemical Recurrence?

• Median time between initial diagnosis and inclusion in the study: 6.3 yrs surveillance,  range 3.3 – 8.0; 5.9 yrs MDT, range 3.5 – 8.3.
• Median PSA at study inclusion: 3.8 surveillance; 5.3 ng/mL MDT.
• PSA doubling time at inclusion: > 3 months in 67% in both arms.
• Nodal metastases: 54% nodal in both arms (16.2% beyond pelvis in surveillance and  12.9% in MDT arm).
• Bone metastases: 35% in surveillance and 41% in MDT arm.
• Patients with 3 metastatic sites: 38.7% in surveillance and 22.6% in the MDT arms

What are the Major Findings of the Ost Trial?

• The key take-away from the study at a median follow-up of 3 years found that the median time for starting ADT in the MDT group was 21 months compared to 13 months for the surveillance arm. 
• “We demonstrated that MDT results in a PSA response in three out of four patients.”
• Of note: 11 men in the MDT group had repeat treatment for polymetastatic progression with only 3 or fewer new lesions, and two men received two additional courses. 
• At 3 years of follow-up, 11 men in the surveillance arm and 5 in the MDT arm developed CRPC.
• The study found improved ADT-free survival in the group with the longer PSA doubling time, i.e. > 3 months. 
• Quality of life was similar in the groups. Six men in the MDT cohort had very minor toxicity.

What are Some Take-Aways from This Small but Well-Done Study?

1. The study design was carefully created using the current state-of-the-art choline PET/CT for registering metastases.

Either multiparametric MRI or biopsy was conducted to ensure no recurrences in the prostate or prostate bed. Current clinical usage of MDT not following the protocol design of this study cannot promise similar results, i.e. staging with the less sensitive CT and technetium bone scans. Studies are in process using the Ga68 PSMA PET/CT and the Axumin scan, both of which are considered more sensitive than the choline PET/CT.

1. The graph in the JCO publication depicting the rate of ADT initiation showed that the slopes of both arms were essentially parallel until about 12-18 months. After that point the MDT slope separated and flattened compared to continued decline in the surveillance group.

This observation suggests that there were adverse, but unrecognized, biologic factors common to patients in both arms that ordained the early development of polymetastatic disease. “This is demonstrated clearly by the current trial — 30% of patients treated with MDT progressed to polymetastatic disease within the first year.”1

It is possible that genomic analysis of patients, such as assessing mutations with circulating tumor DNA or enumerating circulating tumor cells, might allow preselection of optimal candidates for MDT. Dr. Ost [personal communication] indicated that genomic stratification or criteria for eligibility of some type was under consideration. The inclusion in this study of stratification by PSA doubling time is a step in that direction.

The concept of combining immunotherapy with focal radiation for metastatic disease was presented in the February issue of Journal of Clinical Oncology. A Phase I trial reported combining immunotherapy using an anti-PD-1 agent (Pembrolizumab) with stereotactic focal radiation of 1 – 4 metastases in a variety of solid tumors. The underlying theory was that focal radiation would decrease the burden of disease and enhance immunologic response by exposing neo-antigens. 

The November Global Action Plan 6 will try to improve insights on the molecular fingerprint of oligometastatic prostate cancer.

BOTTOM LINE:

The design of this study takes cognizance of the adverse effects of androgen deprivation therapy and asked the question whether focal treatment (MDT) of limited recurrences after primary therapy could delay the need to start ADT.

The conclusion clearly established that delay could be achieved at a median of 8 months. This trial is the first randomized study of its sort and can offer guidance to radiotherapists who have already introduced MDT into their practice. Additional studies will build on this information.

References

1. Ost P, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: A prospective, randomized, multicenter phase II trial. JCO. Feb 2018.

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, & Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”