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Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing the recently published OLIGOPELVIS GETUG P07 trial, a Multicenter Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. And with me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.

This is the citation for this recent publication in European Urology. Now, prostate cancer progresses, as most will know, from initial carcinogenesis within the organ through organ-confined prostate cancer and subsequent metastatic spread. For patients who are to die of the disease, this metastatic burden is most often responsible. Increased use of molecular imaging, particularly, PSMA PET scanning, has led to early identification of a limited metastatic burden, particularly found in pelvic lymph nodes.

And so, this leads to the idea of oligometastatic disease as a potential intermediary pathway between localized disease and wildly metastatic disease. And while this was initially postulated a number of decades ago, it has only recently become more clinically relevant with the ability to diagnose low-volume metastatic disease. And the hypothesis here is that intervention at the time of oligometastatic disease with treatment of these metastatic sites, may actually be curative rather than palliative treatments, which are offered to patients with more widespread metastatic disease.

Now, nodal radiotherapy in prostate cancer is relatively controversial, both in the setting of primary therapy with locally advanced disease, as well as in the salvage post-prostatectomy setting. However, there have been a number of studies assessing metastasis-directed therapy, which is typically then focused on nodal sites, and it has proven to delay the initiation of systemic therapy like ADT.

So, the authors, therefore, suggested that salvage, elective nodal irradiation may treat the micrometastatic disease that would drive future recurrences. The objective of the study is to assess the efficacy of high-dose salvage elective nodal radiotherapy in a prospective fashion. The hypothesis was that elective nodal radiotherapy combined with six months of androgen deprivation would achieve a two-year progression-free survival of at least 70%. The authors included patients with oligorecurrent castration-sensitive prostate cancer who had fewer than six sites of pelvic lymph node disease based on pet CT imaging. For patients who had prior exposure to ADT, at least a six-month washout period was required. Non-castrate testosterone levels were needed, and notably, prior radiotherapy was allowed if this was administered to the prostate or prostate bed. Patients were excluded if they had extra pelvic metastases or were actively treated with androgen deprivation.

Along with this accrued cohort, the patients were divided into four groups. Group A comprises those who had prior radical prostatectomy, no prior radiation, and less than six nodal lesions in the pelvis. Group B with similar, but based on their PET imaging had evidence of a local recurrence in the prostate bed.  Group C had both prior radiotherapy and prior radical prostatectomy. And group D had prior radiotherapy without prior prostatectomy. All patients received IMRT with 54 Gy to the whole pelvis. Additionally, for pathologic nodal lesions, there was an integrated boost to 6 Gy. And in groups A and B who had not received prior radiotherapy, the patients received radiation to the prostate bed in 66 Gy if there was no evidence of local recurrence and 72 Gy for those who had local recurrence. And nodes were contoured in the typical fashion including common iliac, internal and external iliac, presacral, and obturator nodal regions.

The first objective was to assess two-year progression-free survival. And they defined progression as two consecutive PSA increases above their level at inclusion, clinical evidence of progression, or death from any cause. The second objective was to assess biochemical relapse, free survival, overall survival, and time to start of second-line treatments, time to start of palliative androgen deprivation, acute and late toxicities, as well as the quality of life.

The others employed a one-step phase II Fleming design. And they assumed a two-year progression-free survival of 70%. The authors then would require 63 patients to show a statistically significant difference of their assumed 70% from a two-year progression-free survival of at least 50% employing a one-sided alpha of 0.05 and a power of 95%. They included all evaluable patients and used the Kaplan-Meier technique for survival outcomes as well as Cox proportional hazards models to perform post-hoc analyses assessing the prognostic importance of various subgroup variables.

At this point in time, I am now going to hand it over to Zach to walk us through the remainder of the study.

Zachary Klaassen: Thanks Chris. So this is the trial flow chart, which you can see on the right there were 75 patients that were assessed for eligibility; 74 patients were included and subsequently, 67 patients were analyzed including 27 patients in group A, which had prior RP or patients in group B, who had prior RP with prostate bed local relapse; 30 patients in group C who had prior RP plus prostate bed radiotherapy, and six patients in group D, who had prior prostate radiotherapy.

So this is table one, patient characteristics according to patient group and the authors, by way of comparison grouped A plus B together and C plus D together. You can see that the median age was in the late sixties for both groups. The most common ISUP score was ISUB group three at 58% in group A plus B and group ISUP grade two for group C plus D at 44%.

The most common tumor stage for group A plus B was 55% at pT3. And for group C plus D was also 50% at pT3. The majority of patients did not have pathological node involvement, 84% in group A plus B and 83% in group C plus D. The most common number of PET-positive pelvic lymph nodes was one at 61% for both groups and followed by two positive lymph nodes at 23% in group A plus B and 25% in group C plus D. The median PSA at baseline was just under four for both groups. The median PSA doubling time was 4.6 months for group A plus B, and 5.2 months for group C plus D. And the median time between diagnosis at the initiation of treatment was 27 months in group A plus B and 81 months in group C plus D.

This is the number of patients presenting with residual two-year toxicity.  You can see the toxicities on the left.  In the middle is their baseline toxicity, and on the right is the two-year toxicity. By way of summary, there was very little grade three toxicity at two years. You can see urinary toxicity in 4% of patients, sexual toxicity in 2% of patients, and a minimal change from baseline in grade one toxicity of anal and rectal toxicity of 1.5% to 14%, bowel toxicity of 1.5% to 16%, and diarrhea from 3% to 8% at two years.

This is the quality of life by QLQ-PR25 scores over time. You can see on the bottom, sexual activity, urinary symptoms, bowel symptoms, and hormonal treatment-related symptoms. For each block on the far left, is inclusion followed by moving to the right all the way through month 24.  And generally, to summarize, quality of life was essentially relatively stable over the course of treatment for all of these domains.

This is the Kaplan-Meier estimate of the outcomes. On the left is biochemical clinical progression-free survival for all 67 patients. The median biochemical clinical progression-free survival was 45.3 months with a two-year PFS rate of 81%, and a three-year PFS rate of 58%. In the middle is the time to start secondary treatment with a median time of 49.8 months. And on the right is biochemical relapse-free survival with a median of 25.9 months.

So, a swimmer plot of individual patient PSA response, the green line is time to progression or death or last follow-up. The gray is biochemical relapse. Red Xs are progression. And you can see in summary for this figure, the biochemical-free survival rates at two years was 58%, and at three years was 46%.

This is the ADT-free survival Kaplan-Meier curve. You can see here, the median ADT-free survival was 51.9 months among all 67 patients.

This table looks at the pattern of relapse at progression as assessed by the TNM classification based on this group A plus B and C plus D delineation we saw previously.  In terms of the prostate bed in group A plus B, 6.5% recurrence compared to 11% in group C plus D,  N1 disease, 16% group A plus B and 14% in group C plus D, M1A 19% in group A plus B, and up to 39% in C plus D. Again, a big difference in M1B recurrence, 6.5% in group A plus B and 28% in group C plus D.  And finally, M1C is comparable between the two groups at 6.5% in A plus B and 5.5% and C plus D.

This is the table for predictors of progression. Looking at PSA at baseline, ISUP at diagnosis, time from diagnosis to initiation of treatment, the number of nodes, PSA doubling time, history of previous ADT, the treatment group, and time to testosterone recovery, and you can see that among this multi-variable analysis, only the treatment group A plus B versus C plus D was statistically significant with a hazard ratio of 0.34 and a 95% confidence interval of 0.17 to 0.68.

And finally, this is the biochemical clinical progression-free survival delineated by group A plus B, which is in blue compared to group C, which is in red. And you can see that at 12 months, a clear and steady splitting of the curves as delineated above.

So several discussion points from this trial, the six months of ADT plus salvage high-dose pelvic radiotherapy in patients with oligometastatic relapse identified on PET imaging, prolonged PFS with limited toxicity with a median PFS of 45.3 months and a time to ADT of 51.9 months, salvage radiotherapy plus six months of ADT may increase progression-free survival, as well as delay the need for palliative ADT.

Importantly, tumor control was achieved with low toxicity, despite high doses of radiotherapy close to the bladder and intestines with few grade three toxicities reported. And importantly as well, this is achieved among patients even with a history of prostate bed radiotherapy.

So in conclusion, combined high-dose selective salvage pelvic radiotherapy and ADT appear to prolong tumor control in oligorecurrent pelvic node relapse in prostate cancer. A significant proportion of patients were still in complete remission three years after the procedure. And this was at a cost of only limited toxicity. And finally, this study showed initial evidence of benefit, but a randomized trial is required to confirm these findings.

Thank you very much. And we hope you enjoyed this UroToday Journal Club discussion.