SABR to oligometastases slows progression via immune response

Stereotactic Ablative Body Radiation (SABR, or sometimes, SBRT) significantly slowed metastatic progression in men with 3 or fewer metastases (oligometastatic). SABR is a form of concentrated radiation accomplished in 1-5 treatments.

The ORIOLE trial has been previously described in detail here. To recap, it was a small (Phase 2) randomized trial with 36 men treated with SABR to bone scan/CT-detected oligometastases. There were 18 men in the untreated control group. The men were followed for 6 months to see if there was any progression of their cancer. Progression was defined as either PSA progression or new metastases detected on bone scan/CT or physical symptoms of decline (e.g., pain). Of course, with only 6 months of follow-up, most of the detected progression was PSA progression. Phuoc Tran, the lead investigator of the ORIOLE trial, reported the 6-month results here:

• Progression-free survival (PFS) was 81% in the SABR group vs 39% in the control group.
• Median PFS was not yet reached in the SABR group vs 5.8 months in the control group.
• The time to progression was increased by 70% by the treatment.
• Progression has not been reached among those treated patients followed for over a year.

Although patients were only treated for metastases discovered on a bone scan/CT, they were also given a PSMA-based PET scan (DCFPyL). Those in whom no additional metastases were discovered by the PET scan fared better:

• PFS was 84% in the fully treated group vs 36% in those with undiscovered metastases.
• Median PFS was not reached in the fully-treated group vs 11.8 months in those with undiscovered metastases.
• Distant metastasis-free survival (i.e., metastases distant from the ones that were treated) was 29 months in the fully-treated group vs 6 months in those with undiscovered metastases.

PFS in men in whom there were any untreated metastases was not improved compared to untreated men. This seems to be an all-or-nothing sort of thing.

SBRT has been found in lab studies to elicit a strong immune response. It releases cancer antigens into the bloodstream that are detected by T-cells, which become activated to find more cancer. That T cell response to radiation is thought to contribute to its effectiveness (called "the abscopal effect"). The investigators tracked the T cell response and found a significant response in the SABR-treated men.

Progression-free survival when most of the progression is PSA progression is not the endpoint we need to evaluate this therapy. SABR "treats" PSA. "Treating PSA" would occur if the radiation only provides excellent local control, while not necessarily delaying progression elsewhere. PSA is secreted in proportion to the size of the tumors, so treating only the tumors will do nothing to stop the micrometastases that are elsewhere. However, the strong T-cell response found by this study suggests that there may be a true delay in progression and not only a delay in PSA. Also, the fact that distant metastases were delayed by almost 2 years among those who had all of their PSMA-detected metastases irradiated, suggests a true response.

This is an important first step toward discovering whether oligometastasis-directed therapy provides a benefit, and how it works. It does not yet provide the answer to whether there is a survival benefit to such therapy. It also does not answer the question of whether ADT can be delayed when radiation has been given. There are several, larger clinical trials that will answer those questions more definitively. Meanwhile, the patient with rising PSA after prostate therapy should consider:

1. A PSMA-based PET scan (available in some clinical trials, and probably widely available within a year).
2. Talking to a radiation oncologist about SABR treatment of metastases if all discovered metastases are in places where it is entirely safe to treat them
3. Not forgoing ADT adjuvant to SABR treatment until there is more proof.

The definition of SECOND biochemical recurrence (after prostatectomy AND salvage radiation)

There is no standard definition of SECOND biochemical (PSA-detected) recurrence (BCR); that is, after both prostatectomy and salvage radiation (SRT). There are two reasons to have a standard definition of second BCR:

1. Time for next treatment: BCR (after any treatment) is the first indicator of treatment failure, and a signal that it may be time to consider additional treatment. It is not at all clear that immediate additional treatments are beneficial. If a treatment becomes the standard of care after biochemical failure, then it will be necessary to define the PSA or PSA doubling time (PSADT) at which that treatment should begin.
2. Comparison among radiation protocols: Lacking randomized clinical trials among all the variables of when and how salvage radiation are given (pathological characteristics, PSA, PSADT, radiation dose, adjuvant ADT, prostate bed radiation, radiation of pelvic lymph nodes), we can only look at effectiveness across studies to help us hypothesize that one strategy might be better than another. It helps if we have a consistent definition of success.

Miyake et al. looked at three definitions of second BCR:

1. NARA definition: PSA never falls below 0.2 ng/ml; or, it falls below 0.2 ng/ml but later rises over it in two consecutive readings.
2. RTOG 9601 definition: any post-SRT PSA over 0.5 ng/ml; or, nadir + 0.3 ng/ml; or the start of hormone therapy.
3. GETUG definition: nadir + 0.5

They evaluated 118 patients using the 3 definitions. With 49 months of median follow-up after salvage radiation:

• The Nara definition had the highest rate of second BCR; 53%, 45% and 40% for Nara,  RTOG and GETUG respectively.
• Gleason score and Pre-SRT PSA independently predicted Nara BCR, while negative margins and PSADT also predicted RTOG and GETUG BCR.
• There were no discrete cut-offs of the patient characteristics that reliably predicted BCR by any definition

It's worth noting that the definitions may differ for study entry and endpoint (it is usually called "biochemical progression" when used as an endpoint). Many clinical trials use the 0.2 ng/ml definition for the second BCR too.  This trial used PSA≥ 0.2 ng/ml or 3 consecutive rises after RP or SRT. We recently saw that another RTOG trial, the SPPORT trial, used a BCR endpoint definition of nadir + 2 because it correlated well with clinical recurrence. This is the definition advocated by PCWG2.

It is sometimes necessary to define a THIRD BCR as an endpoint to determine whether a therapy that began after a second BCR was successful. For example, an ongoing trial of hormonal therapies for SRT-recurrent men uses a second BCR definition of PSA > 0.5 ng/ml and PSADT ≤ 9 months, and a third BCR definition of a confirmed 25% rise in PSA and nadir + 2 during therapy, and a fourth BCR definition of a confirmed PSA > 0.2 after hormonal therapy.

The definition for FIRST BCR of a confirmed PSA after prostatectomy of 0.2 ng/ml was an artifact of the current lowest discernible PSA before the 21st century, which was 0.1 ng/ml at the time. The American Urological Association decided that anything higher than that would be deemed a BCR. The "ARTISTIC" meta-analysis established that for most patients, it was unnecessary to establish a PSA for first BCR below 0.1 or 0.2.

BCR is just one of a number of elements to be evaluated after SRT. A BCR with a high Decipher score may suggest that immediate salvage ADT is appropriate. With the new generation of PET scans, which can detect metastases at low PSAs, it may sometimes be beneficial to treat pelvic lymph node metastases and possibly distant metastases if SRT had only included the prostate bed.

This small, retrospective study will not establish a new definition, but it does raise the interesting question of whether we need a standard definition, or whether the definition ought to depend upon the purpose for which it is used. If we have definitive evidence that early treatment after failed SRT is beneficial, that will force researchers to investigate the optimum PSA (or PSADT) cutpoint. Until then, the PCWG2 definition (PSA≥ nadir + 2.0), PCWG3 definition (PSA≥nadir+ 1.0), or the combination of PSA and PSA doubling time used in the EMBARK protocol (PSA≥1 and PSADT≤ 9 months) are all reasonable.

PSMA PET finds more cancer than Axumin

A PSMA PET scan (Ga-68-PSMA-11) detected more sites of cancer than an Axumin PET scan in the same recurrent patients. This prospective clinical trial was  conducted among 50 men at UCLA in 2018. All men had post-prostatectomy PSA from 0.2- 2.0 ng/ml.  The Calais et al. findings are summarized in the following table:

	Ga-68-PSMA-11	Axumin
Detected - % of patients	56%	26%
Prostate bed	14%	18%
Pelvic lymph nodes	38%	8%
Extra-pelvic lesions	16%	0%

The two scans performed equally well at detecting recurrence in the prostate bed, but the PSMA PET scan was able to detect more cancerous pelvic lymph nodes and non-regional metastases. The surprising result is that more recurrences are attributable to pelvic lymph nodes (stage N1) or to extra-pelvic metastases (stage M) than to cancer in the prostate bed. If this is true of all recurrent men, it indicates that salvage whole pelvic radiation is usually preferred over salvage prostate bed radiation. We saw (see this link) that salvage whole pelvic radiation improved progression-free survival compared to salvage prostate bed-only radiation. But in that SPPORT trial, the authors noted that the improvement did not hold up at low PSAs. Even the best PSMA PET/MRI has a tumor size detection limit of about 4 mm. If cancer in the pelvic lymph nodes is still curable, it may be necessary to treat cancer while it is still undetectable.

The detection rate by PSA was as follows, but is based on small numbers of patients in each PSA group. The differences in the detection rates are statistically significant for PSAs over 0.5:

PSA (ng/ml)	Ga-68-PSMA-11	Axumin
0.2-0.5 (n=26)	46%	27%
0.51-1.00 (n=18)	67%	28%
1.01-2.00 (n=6)	67%	17%

The other PSMA-based PET scan, DCFPyL, has completed recruiting.

(update 12/19/20) In a meta-analysis - in different patients - the detection rates were as follows:

PSA (ng/ml)	Ga-68-PSMA-11 n = 3,217 in 38 studies	Axumin n = 482 in 6 studies
0.2-0.5	45%	37%
0.51-1.00	59%	48%
1.01-2.00	80%	62%

The difference for PSAs from 1-2 ng/ml is statistically significant.

FDA has approved the Ga-68-PSMA PET/CT at UCLA and UCSF.