Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're talking about a recent publication entitled, The Addition of Androgen Deprivation Therapy and Pelvic Lymph Node Treatment to Prostate Bed Salvage Radiotherapy, the NRG RTOG 0534 SPPORT trial, an international, multicenter, randomized Phase III trial.

I'm Chris Wallis, an assistant professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, assistant professor in the Division of Urology at the Medical College of Georgia.

You can see here, the citation for this recent publication in Lancet Oncology, led by Dr. Pollack.

By way of background, biochemical recurrence following prostatectomy is relatively common for men with prostate cancer. The rates vary, between approximately five and 50%, based on clinical pathologic features. In historical trials of adjuvant radiation therapy among patients with extracapsular extension, positive surgical margins, or seminal vesicle invasion. Rates of biochemical failure were high, among patients who did not receive adjuvant treatments, reaching as high as 60% to 10 years. However, in contrast to this adjuvant approach, recent data including the meta-analytic collaborative approach in the artistic publication, support the use of an early salvage radiation approach. However, we know that some patients do fail following salvage prostate bed radiation, and therefore, there's room for optimization of this treatment paradigm.

The goal of SPPORT is to address two key management options in prostate cancer patients who are undergoing salvage radiation. The first is, is there an incremental benefit to the addition of short term androgen deprivation therapy to standard salvage prostate bed radiation? This is a question that's been addressed in two prior randomized trials, but not fully resolved in clinical practice, hasn't fallen entirely in line. The second is, is there an additional benefit from the addition of pelvic lymph node radiation at the time of salvage prostate bed radiation?

So to address these questions, the authors performed an international, multicenter, randomized controlled trial, at 283 RTOG/NRG sites in the United States, Canada, and Israel. They included men who'd undergo prostatectomy for adenocarcinoma of the prostate, who had either a persistently positive or initially undetectable, and then rising PSA, reaching between 0.1 and two nanograms per milliliter.

In terms of pathologic characteristics, patients that had to have pT2 or three disease, N0 or NX disease, and Gleason scores of nine or less. They've had a Zubrod performance status of zero to one. And age 18 years or older. Adequate marrow and liver function. And a serum testosterone greater than 40%, the lower limit of normal.

Patients were excluded if they had metastatic disease on CT or bone scan. A palpable prostatic fossa mass. Pathologic evidence of nodal involvement. Had received androgen deprivation therapy for more than three months after their prostatectomy, or had received other prostate cancer treatments, including chemotherapy with prostate cancer, or an alternative prostate cancer treatment prior to the radical prostatectomy. Further, patients with other cancer diagnoses in the last five years, or history of inflammatory bowel disease or other comorbidities precluding treatment were excluded.

The authors randomized patients in a 1:1:1 fashion to the three treatment regimes, including prostate bed radiation alone, prostate bed radiation with short-term ADT, or prostate bed radiation with pelvic lymph node radiation, as well as short-term ADT. Stratification of the randomization was performed according to the presence of seminal vesicle invasion, Gleason score, baseline PSA, and pathologic stage.

Radiotherapy was given in a standard approach, using the prostate range of total doses allowed between 64.8 and 70.2 Gy, and 1.8 Gy daily fractions.

In group three, pelvic lymph nodes were targeted to include the obturator, external iliac, proximal iliac, presacral and common iliac nodes, up to level of L5 and S1, utilizing the vascular structures for landmarking. These regions were treated up to 45 Gy at 1.8 Gy per fraction for five weeks, followed by a volume reduction for the remaining dose delivered to the prostate bed.

In groups two and three, short-term ADT was used, and started within six weeks of registration. This was two months prior to the initiation of radiation, and was continued for a total of four to six months. Patients received initially, an antiandrogen, as well as an LHRH agonist.

In terms of pre-treatment evaluation, patients underwent standard blood work, as well as an AUA symptom index.

In terms of follow up evaluation, they underwent quality of life and neurocognitive assessments at three, six and 12 months, and then every six months until year six, and then annually thereafter.

Adverse event assessment was performed at every protocol specified clinic visit. And at week six of radiotherapy, patients had blood work, as well as an AUA symptom index.

Moving forward, PSAs were tested at six weeks, and then three months. Following this, it was every three months for the first two years, and every six months thereafter. Liver function testing was performed at six weeks, three months, and six months after radiation. And CBC was checked at six weeks and six months, with cross-section imaging, including CT and MRI, as well as bone scan performed where clinically indicated.

The primary outcomes, freedom from progression at five years. And this was the first occurrence of biochemical failure, according to the Phoenix definition, clinical failure, or death from any cause.

Secondary outcomes included, local failure, regional failure, distant metastases, biochemical failure according to the Phoenix definition, and alternate biochemical failure definition, which included a PSA greater than or equal to 0.4, with a second rise or the start of salvage radiation, castration resistant disease, cause specific mortality, overall survival, adverse events, and time from the initiation of therapy to late-grade toxicity.

The authors assessed the primary hypothesis, the treatment intensification would improve biochemical control. The anticipated five year freedom from biochemical failure was 70% in the prostate bed radiation alone arm. And they hypothesized, the 10% improvement for patients receiving short-term ADT, and a 20% improvement for patients receiving short-term ADT and pelvic nodal radiotherapy.

A backward elimination rule was used for the sample size calculation with three one-sided comparisons. This was first, that group three was better than both group one and two. The second, that group three was not better than group two, but that group two is better than group one. And the third was that, neither group two or three were better than group one.

Overall, they used a one-sided alpha of 0.025, which resulted in a calculated sample size of 529 patients per group, and they adjusted this to 588 patients per group.

Protocol strongly discouraged the use of second salvage therapy before the primary endpoint, to allow for a cleaner analysis.

Three interim lyses were planned for early stopping at 397, 794 and 1,191 patients. The third of these met criteria for efficacy, and thus, concluded the trial. Kaplan Meier technique with log-rank tests, and Cox proportional hazards models were used for the primary outcome adjudication as well as overall survival.

All secondary endpoints were assessed using cumulative incidents, with death treated as a competing event.

There were two post hoc endpoints added, including metastasis-free survival in the time to the initiation of second salvage therapy with ADT. And additional post hoc analyses, including freedom from progression, divided according to mean median pre-treatment PSA and by stratification factors was performed, as was stratification of the assessment of the initiation of second salvage therapy by median pre-treatment PSA, as well as freedom from progression, according to the duration of ADT received.

Now, I'm going to hand it over to Zach, to walk us through the results of the SPPORT trial.

Zachary Klaassen:

Thanks so much for that comprehensive introduction, Chris.

This is the trial profile, and I've annotated the groups here, just to remind everybody about the three group schema for this trial.

Group one included 592 patients that were assigned to prostate bed radiotherapy alone. Ultimately 568, four of these are eligible for analysis. Group two included 602 patients assigned to prostate bed radiotherapy plus short-term ADT, which ultimately, led to 578 patients included in the analysis. And then finally, group three included 598 patients assigned to pelvic lymph node therapy, radiotherapy plus prostate bed radiotherapy plus short-term ADT. And this ultimately, resulted in 574 patients included in the analysis.

Moving forward through the results, I will refer to these as group one, two, and three, for simplicity.

This is the table one baseline demographics. This is a large table, so I've broken it down into two slides. And you can see here, that the median age for all three groups was 64 years of age. Majority of these patients were Caucasian, at more than 80%, however, there was roughly 12 to 13% black or African American.

Moving down to the performance status, majority, more than 90% had a Zubrod performance status of zero. With regards to seminal vesicle involvement, the majority, more than 85%, did not have seminal vesicle involvement.

In looking at the pathological tumor stage, we can see that, more than 80% of patients were either T2 or T3A.

With regards to Gleason score, the most common Gleason scores were Gleason 3+4 and 4+3.

And with regards to positive margins at the time of prostatectomy, just over 50% of patients had positive margins.

Looking at the second half of this table, in terms of patients that had a pelvic lymph node dissection, roughly two thirds of patients, the median number of lymph nodes examined was five to six. The median pre-radiotherapy baseline PSA was 0.32 for group one, 0.40 for group two, and 0.32 for group three.

Looking at the median time from surgery to randomization, it was just over two years for all three groups. And in terms of postoperative PSA doubling time, the most common group of PSA doubling time was greater than six months, to less than 12 months.

So this is the Kaplan-Meier estimates. We'll look at several of these over the next couple of slides. On the left is freedom from progression. And we can see here that, for group one in red, group two in blue, and group three in green, the five year rate of freedom from progression for group one was 70.9%, for group two was 81.3%, and for group three was 87.4%. And you can see here that, for the five year rate comparisons were all significant with regards to group three versus group one, group two versus group one, and group three versus group two. Moving to the right of the slide, this is for overall survival. Same color scheme for this figure. And you can see, looking at these same group comparisons, there was no difference in overall survival between these groups.

These are cumulative incidents curves, looking at prostate cancer death on the left, and distant metastases on the right. And again, you can see that, when group three was compared to group one for prostate cancer death, this was statistically significant. Whereas, the remaining comparisons, two versus one and three versus two, was not significant. Looking at the right of the slide for distant metastases, we see that group three versus group one, and group three versus group two, was statistically significant, with regards to distant metastases. Whereas, group two versus group one was not.

This is a busy table looking at the univariable and multivariable Cox regression analysis. On the far right of this table is the multivariable analysis, which is what we'll focus on. And I included, in the highlighted boxes, the statistically significant comparisons between groups.

So to summarize this, if we look at freedom from progression, distant metastases, biochemical failure, alternative biochemical failure, time to second salvage ADT, we see that for all of these analyses, with regards to group three versus group one, group two versus group one, and group three versus group two, these were all statistically significant analyses.

If we look at local failure and regional failure, we see that there was statistically significant differences between group three and group one, and group two and group one, but there was no difference for these two outcomes for group three versus group two.

Finally, if we look at prostate cancer death, we see that group three versus group one was statistically significant. If we look at castration resistant disease, group three versus group one, and group three versus group two, was statistically significant.

And finally, metastasis-free survival, as Chris mentioned, a post hoc analysis, group three versus group one was statistically significant.

This slide looks at the Forest plots showing freedom from progression in the three treatment groups. And so, this is group two versus group one, so prostate bed radiotherapy plus short-term ADT, versus prostate bed radiotherapy alone. But we could see that generally, this favors group two with the addition of ADT, except for patients with Gleason 8-9 prostate cancer.

This Forest plot looks at group three versus group two, so the added benefit of pelvic lymph node radiotherapy. And we can see here that, looking at baseline PSA, Gleason score, pathology, and seminal vesicle involvement, the hazard ratios are all on the left, which favors group three. But the 95% confidence, it rolls cross one for all of these analyses.

In terms of group three versus group one, this is the benefit of short-term ADT plus pelvic lymph node radiotherapy, versus just prostate bed radiotherapy alone. We see that overwhelmingly, there is a favor for group three in all of these subgroup analyses, as you can see at the bottom right of the screen.

These are the cumulative incidence curves, looking at alternative biochemical failure and second salvage ADT. Again, with the same color scheme of, red being group one, blue BR being group two, and green being group three. There were significant differences for both of these outcomes, with regards to group three versus group one, group two versus group one, and group three versus group two, with the early and wide splitting of the curves.

With regards to adverse events of interest, the trial set a statistically significant P value of less 0.025. And so, I've highlighted again, the statistically significant adverse events. As you can see on the far right, this is group three versus group two. To the left of that, is group two versus group one.

And we can see that, for all grade two and grade three, there was significant difference, so added adverse events, with in treatment intensification for group two versus group one, and group three versus group two. This is in the acute adverse setting.

So looking at bone marrow in the acute adverse setting, only group three versus group two had significant differences in adverse events. And with regards to acute gastrointestinal adverse events, grade two was significant for group three versus group two.

However, looking at the late adverse events, the only statistically significant difference was in grade two blood or bone marrow adverse events, when we were comparing the group three patients versus the group two patients. Otherwise, there was no difference in late adverse events.

So several discussion points from the SPPORT trial. There was two key clinical questions addressed by SPPORT central to salvage radiotherapy management.

First question was, what is the potential benefit of adding short-term ADT to standard prostate bed radiotherapy? And this trial showed that, there was a benefit to short-term ADT.

Secondly, what is the potential benefit of adding pelvic lymph node radiotherapy to this combination? Again, this trial showed a significant benefit for adding this additional radiotherapy.

With regards to the freedom from progression endpoints in SPPORT, this was driven by the Phoenix definition of biochemical failure, because of the stronger associations with clinical failure, compared to the AUA definition. Which is, a PSA greater or equal to 0.2, and a confirmatory PSA greater than or equal to 2.2.

A failure event would be based on a PSA greater than two, which is notable after radical prostatectomy, which often triggers intervention.

SPPORT is the first post-radical prostatectomy trial to test the benefit, and show benefit, of increasing the radiotherapy field size, to treat the pelvic lymph nodes.

So in conclusion, the results of this randomized trial established the benefit of adding short-term ADT to prostate bed radiotherapy, to prevent progression in prostate cancer. Additionally, these are the first such findings to show that extending salvage radiotherapy to treat pelvic lymph nodes, when combined with short-term ADT, results in meaningful reductions in progression after prostatectomy, in patients with prostate cancer.

Thank very for your attention, and we hope enjoyed this UroToday Journal Club discussion of the SPPORT trial, recently published in the Lancet.