Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today we're discussing the RAVES trial, assessing adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy. I'm Chris Wallis, a Fellow in urologic oncology at Vanderbilt, and with me is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. Here's the citation for the recently published RAVES trial, and we'll get into discussing it now.

By way of background, most UroToday readers and viewers will know that there's a significant body of evidence looking at the role of adjuvant radiotherapy for men with adverse pathological findings at the time of radical prostatectomy. Most of these trials were conducted many years ago and assessed the role of upfront adjuvant radiotherapy compared to a delayed treatment approach with a combination of late salvage radiotherapy and salvage hormonal therapies. On the basis of these data, we don't really have important conclusions to define current practice today. When we analyze the results of these four trials pooled together, we can see that the use of adjuvant radiation, again, compared to a very conservative non-interventional control, improves biochemical progression-free survival, has potentially an equivocal impact on metastasis-free survival, and certainly has no effect on overall survival, despite the benefits seen in the SWOG trial.

In spite of these data, we have guidelines from the AUA and ASTRO suggesting that a physician should offer adjuvant radiotherapy to all patients with adverse pathological findings at the time of prostatectomy. This, however, does not reflect contemporary practice patterns in which most physicians have taken an alternative approach using salvage radiotherapy. The data from Dr. Trock and colleagues at Johns Hopkins provided some of the first evidence to support the use of a salvage radiotherapy approach. Subsequent data showed that earlier use of salvage radiotherapy was associated with better outcomes. Modern practice in the absence of evidence evolved to the use of early salvage radiotherapy for most patients. However, in recent weeks, we now have randomized data to support such an approach. The RAVES trial set out to assess the hypothesis that for patients with pT3 disease or positive margins following radical prostatectomy, observation with early salvage radiotherapy is non-inferior to standard treatment of adjuvant radiotherapy with respect to biochemical recurrence.

This is a figure presented at ASTRO 2019 looking at the study schema for the RAVES trial. Again, men were enrolled if they had positive margins, EPE, or seminal vesicle invasion. Key, unlike prior studies, men had to have undetectable PSA. This is a truly adjuvant use. One-to-one randomization was undertaken to adjuvant radiotherapy versus a surveillance approach with planned early salvage radiotherapy. This was a Phase III randomized controlled non-inferiority trial. This stands out unique compared to other recent publications of the GETUG-17 trial and the RADICALS-RT trial, which were both superiority in design. This was a non-inferiority trial, and this was conducted in 32 oncology centers in Australia and New Zealand. Key patient-level inclusion criteria included all men who had prior radical prostatectomy and evidence of positive surgical margins, extraprostatic extension, or seminal vesicle invasion.

Again, PSAs had to be undetectable post-operatively and they had to be able to start radiotherapy within four months of surgery. This trial was restricted to men with good performance status and further excluded men who had a history of prior radiotherapy or androgen deprivation, those who had a total hip replacement, and those who had evidence of nodal or distant metastases. One-to-one randomization was undertaken to adjuvant radiotherapy or the observation approach with stratification according to seminal vesicle invasion, Gleason score, preoperative PSA, surgical margin status, and institution.

In terms of the nature of radiotherapy intervention, this trial was relatively robust in the pre-recruitment compliance and credentialing of the radiotherapists. All trial-related treatment plans underwent pretreatment review and targeting was done according to guidelines of the Faculty of Radiation Oncology Genito-Urinary Group. Radiation was administered in 64 gray and 32 fractions, with salvage radiation initiated for PSAs greater than 0.2 and keeping with an early salvage radiation definition. Notably and different than other trials that have recently been presented, concurrent ADT was not allowed in the RAVES trial.

The primary outcome for this trial was freedom from biochemical progression. That was defined as the first PSA greater than 0.4 and rising following radiotherapy. Secondary outcomes included time to the initiation of ADT, time to clinical progression, overall survival, quality of life, mental health, adverse events, and quality-adjusted life years.

Patients were assessed in the adjuvant group with PSA six weeks following their radiotherapy, and then every six months. Follow-up was slightly closer in the early salvage group in order to identify patients with early biochemical recurrence. PSA checks were performed every three months for five years, and then every six months thereafter. The authors presumed a 74% five-year biochemical progression-free survival based on the results of the EORTC, and then considered that salvage radiotherapy would be considered non-inferior if this differed by no more than 10% from the adjuvant arm. That's assuming proportional hazards. This gave a hazard ratio of 1.48 and a sample size of 470 patients to give 80% power. However, in 2015, after 300 patients were randomly assigned, there was a futility analysis undertaken, demonstrating a significantly lower event rate than predicted, and thus the study closed to recruitment at that time.

An analysis was undertaken using Cox proportional hazards models and performed in both the intention to treat and per-protocol populations. At this time, I'll hand it over to Dr. Klaassen to discuss the results and implications of this trial.

Zachary Klaassen: Thanks, Chris. In this trial, there were 333 patients enrolled and randomly allocated, 166 were allocated to adjuvant radiotherapy, and included the intention to treat analysis, as well as 167 patients that were allocated to salvage radiotherapy. There were 154 patients that completed follow-up in the adjuvant group and 153 that were included in the salvage radiotherapy group that completed follow-up.

This table is the baseline characteristics. You can see adjuvant radiotherapy on the left and salvage radiotherapy on the right. This is quite standard for prostate cancer population with a median age of 63 years. You can see that the majority of these patients were ECOG performance status zero, so very good performance status. The median PSA in the adjuvant therapy group was 7.4, as well as 7.4 in the salvage radiotherapy group. You can see that the majority of these patients were Gleason 7, 81% for adjuvant, and 83% for salvage radiotherapy. About two-thirds of the patients had positive surgical margins, and about one-fifth of the patients had seminal vesicle involvement.

This Kaplan–Meier curve shows the freedom from radiotherapy for patients in the salvage radiotherapy group. You can see here that the median time from radical prostatectomy was about six years from their initial treatment. This basically shows that the majority of these patients lasted several years before they actually had their salvage radiotherapy.

This figure here shows freedom for biochemical progression by treatment group in the intention to treat analysis. The Kaplan-Meier curve on the left in red shows salvage radiotherapy, whereas in blue shows adjuvant radiotherapy. You can see that the five-year freedom from biochemical progression in the adjuvant radiotherapy group was 86% compared to 87% in the salvage radiotherapy group, with an insignificant stratified hazard ratio of 1.12, a 95% confidence interval of 0.65 to 1.90.

This is a forest plot for freedom from biochemical progression according to known prognostic factors. Just a quick overview of this figure shows that all of these subgroups cross the hazard ratio of one. All of these were non-significant. You can see here for seminal vesicle invasion, slightly favoring salvage radiotherapy, really no difference based on PSA, as well as positive surgical margins and Gleason score. You can see here that the overall non-stratified hazard ratio was non-significant at 1.15 and a confidence interval of 0.67 to 1.95.

This figure here shows freedom from loco-regional or distant progression by treatment arm, once again, salvage radiotherapy in red and adjuvant radiotherapy in black. Very close lines here, the five-year freedom from loco-regional or distant progression of the adjuvant arm was 96%, as well as 96% in the salvage radiotherapy arm.

These results here show the time to initiation of androgen deprivation therapy. The adjuvant arm is in yellow and the salvage arm is in purple, with a nonsignificant hazard ratio of 0.70 and a 95% confidence interval of 0.32 to 1.52.

Importantly, the toxicity here is interesting. In the prevalence of grade two or worse genitourinary toxicities, the adjuvant group is in blue and the salvage radiotherapy group is in red, and so the GU toxicity rate for the salvage arm was 54% compared to a higher rate of 70% in the adjuvant arm, with a likelihood of grade two or worse GU toxicity being lower in the salvage arm, with 0.34 odds ratio and a 95% confidence interval of 0.17 to 0.68.

When we look at the grade two or worse GI toxicity, there's really no difference between the groups, salvage radiotherapy 10%, adjuvant radiotherapy 14%, with an insignificant odds ratio of 0.48 and a 95% confidence interval of 0.05 to 4.88.

Several important discussion points from the RAVES trial, high rates of freedom for biochemical progression were achieved using 64 gray, which is a modest dose in the salvage setting, in that it may get up to about 70 gray in the previous trials. The five-year freedom from biochemical progression for the adjuvant group in the RAVES trial was 86%, which was better than those in the EORTC 22911 trial adjuvant group of 74%.

Really, is this because there's better selection of patients? In this trial for RAVES, those with high-risk of residual local disease but low-risk of metastasis were included, as to included a T3 or positive surgical margin patients, but all these patients had an undetectable PSA and no seminal vesicle invasion.

The question is, should we have salvage radiotherapy with or without androgen deprivation therapy? Certainly, we've had previous publication a couple of years ago from the SPPORT trial that showed that five-year freedom from disease progression benefit with the addition of pelvic nodal treatment to the prostate bed plus ADT. What's been interesting over the last couple of years is this is a paper from the European Association of Urology that has started to sort of risk stratify low-risk biochemical recurrence or high-risk biochemical recurrence. You can see here on this table on the right, those that had biochemical recurrence after radical prostatectomy were considered low-risk if they had a PSA doubling time greater than one year and a pathological Gleason score of less than eight, whereas high-risk biochemical recurrence was denoted as having a PSA doubling time less than or equal to one year or a pathological Gleason score of 8 to 10.

In terms of biochemical recurrence after radiation therapy, low-risk of BCR was defined as an interval from primary therapy to biochemical failure of greater than 18 months and a biopsy Gleason score less than eight, whereas high-risk biochemical recurrence after radiotherapy was defined as an interval from primary therapy to biochemical or a failure of less than or equal to 18 months or a biopsy Gleason score of 8 to 10. Really, there may be an opportunity based on these sort of characteristics of low- or high-risk biochemical recurrence for either intensification or de-intensification of treatment. This will be interesting to see results from this sort of stratification in the coming years.

In conclusion, early salvage radiotherapy in RAVES resulted in similar biochemical control to adjuvant radiotherapy. Importantly, this spares approximately 50% of men from pelvic radiotherapy, as this study showed that radiotherapy was associated with significant lower GU toxicity when given in the salvage versus the adjuvant setting. This supports the use of early salvage radiotherapy over adjuvant radiotherapy for patients at high-risk post-prostatectomy.

Thank you for your attention and for joining us for this UroToday Journal Club.