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Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing a recently published paper entitled, "Curative-intent Metastasis-directed Therapies for Molecularly defined Oligorecurrent Prostate Cancer: A Prospective Phase 2 Trial Testing the Oligometastasis Hypothesis." I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and with me today is Zachary Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia.

This is the citation of this recently published work in European Urology, led by Dr. Rachel Glicksman as first author and Dr. Alejandro Berlin as senior author. The concept of oligometastatic was first proposed in 1995, and since that time there has been considerable interest in this disease space. This implies that there is an intermediate space between patients who have localized disease with cancer restricted to the organ of origin and widely metastatic disease with metastases spread throughout the body. In this oligometastatic disease space, patients are expected to have a better prognosis and may have the potential for cure. Now, currently available prospective trials have demonstrated improvement in survival outcomes when local treatment approaches have been applied to these metastatic foci. However, to date, the ability to render a cure is somewhat limited in metastatic disease due to an inability to accurately characterize all metastatic sites.

The question that the authors sought to assess here is whether data could be derived assessing whether patients can be rendered entirely disease-free, i.e. cured, with ablative treatment alone in the absence of systemic therapy for oligometastatic disease. Prostate cancer represents a good model for this oligometastatic treatment paradigm, because firstly, we have a biomarker using PSA, which is sensitive for the early diagnosis of recurrent disease, and we have recently developed novel imaging approaches, which allow for early identification and localization of these metastatic foci.

Recently published data have shown that metastasis-directed therapy may delay the initiation of non-curative ADT approaches, however, the authors here sought to assess whether we could use 18fluoride DCFPyL PET-CT to allow for earlier identification and localization metastatic disease, which could be amenable to treatment with curative intent directed at those sites. To do this, the authors included patients with pathologically confirmed prostate cancer, who had undergone prior treatment with either radical prostatectomy and subsequent postop radiotherapy. There had to be at least 1 year since the cessation of androgen deprivation therapy if this was given concurrently with radiotherapy. The authors defined disease recurrence as three consecutive PSA increases in an absolute PSA between 0.4 and 3 nanograms per milliliter. Patients had to be non-castrated with normal testosterone, and have negative conventional imaging based on CT and bone scan. Patients were excluded if they had prior use of ADT that did not fit the previous criteria, prior use of chemotherapy, or any contraindications to MRI or IV contrast.

The authors then initiated a single-institution, open-label, single-arm phase 2 study, and in doing so, they undertook a PET-MR/CT within 6 weeks of registration introduced. So, they performed a PET-MR, which was followed immediately by a PET-CT. The results of these scans were reported to the patient and the treating physician, and all cases were then discussed at a multidisciplinary tumor board and patients were seen in consultation by urologists and radiation oncologists. On the basis of the multidisciplinary tumor board and patient consultations, patients were then offered metastasis-directed therapy with either surgery, being a salvage node dissection, or SABR with radiation given in three fractions. Following a metastasis-directed therapy, patients were followed up at 2 weeks and then 1, 2, 3, and 6 months. A repeat PET-MR was performed at 4 months following metastasis-directed therapy. The second course of metastasis-directed therapy in the form of SABR was allowed for newly developed PSMA-avid untreated lesions.

The first objective of the study was to determine if 18F-DCFPyL PET-MR/CT could identify early oligorecurrent disease, and this was captured in terms of detection rates and patterns of recurrence. And secondly, the authors sought to determine whether treating PET-MR/CT detected lesions could result in clinical benefit, and they quantify this in terms of biochemical response, which could be either partial or complete. Secondarily, the authors assessed adverse events associated with metastasis-directed therapy, PSA progression, following metastasis-directed therapy, and ADT-free survival.

The authors employed Simon's optimal two-stage phase 2 clinical trial design to test their approach. The first stage required 12 response-evaluable patients be treated, and in stage two, if at least one of the initial 1200 patients had a response, the trial continued to accrue an additional 25 patients. Overall, the study would be deemed effective if at least four objective responses were seen, and based on the literature, the authors expected a 50% detection rate using PSMA PET-MR. The authors performed descriptive statistics and examined the change in PSA as well as response capture using waterfalls and swimmers plots, respectively. Survival data were captured using a Kaplan-Meier technique, and univariable Cox models were used to assess for predictors.

At this point in time, I will pass it over to Dr. Klaassen to walk us through the results.

Zachary Klaassen: Thanks, Chris. In this study, they assessed 87 patients for eligibility and subsequently assessed for multi-disciplinary therapy eligibility with PSMA PET, which was 72 patients. And ultimately, there were 37 patients that were allocated to intervention, including 27 to SABR and 10 to surgery. These are the baseline patient characteristics of the MDT cohort. You can see here that the median age was 60 years. The majority of patients were intermediate risk based on NCCN stratification. In terms of radical prostatectomy and Gleason Score, the most common was Gleason 4 + 3.  The most common T stage was T3b, at 38%, followed by T3a, at 32%. The majority of patients were pN0, at 79%. And the median interval in terms of months from radical prostatectomy to post-operative radiotherapy was 8 months.

In terms of what type of post-op radiation therapy they had, the most common was salvage, at 59%, followed by adjuvant, at 38%. In terms of combining postoperative radiation plus ADT, the majority did not have a combination therapy, at 84%. And then the number of metastases detected on imaging was one at 49% and two at 22%. The location, most commonly, was lymph node metastasis, at 92%, and M1a, a pelvic single lymph node, at 41%, and M1b, multiple pelvic lymph nodes, at 41%.

This diagram looks at patients with their PSMA PET-MR/CT nodal recurrence patterns. You can see here that the majority of the patients were either in the external iliac or another region, in pink, for example, mesorectal. Common iliac was 18%, in purple, presacral was 11%, in yellow, 10% internal iliac, in blue, 9% in the retroperitoneum, in yellow, and 4% for the obturator nodes.

This waterfall plot looks at the maximal biochemical response after MDT. So if you look at this plot, on the left are the red patients. There were 5 of them that had PSA progression greater than baseline. And impressively, the rest of these patients had at least a complete, partial, or minimal response. The complete responders, undetectable PSA, are located in blue on the right, the partial responders, with a PSA decline of 50 to 99% from baseline, are in green, and the minimal responders, PSA decline of 1% to 49% from baseline, is in yellow.

This swimmers plot of biochemical response over time after MDT shows that there were several complete responders.  At the top, you can see here, a lot of partial responders, which you can see in green. And then patients ultimately did have PSA progression greater than the baseline, which is noted by the red diamond. This Kaplan-Meier curve looks at PSA progression-free survival. The median time to PSA progression was 17.7 months, with a 95% confidence interval of 11 to not reach. This Kaplan-Meier curve looks at hormonal therapy-free survival, which is impressive. You can see here that the median time to hormonal therapy has not been reached yet. In terms of toxicity, you can see here that there was a grade 2 DVT in one patient undergoing surgery, as well as one grade 3 ureteral injuries in another patient undergoing surgery.

So, several discussion points from this phase 2 trial, in that this study found that PSMA PET-CT/MR identified the disease in 78% of patients, and MDT-rendered biochemical control in 60% of patients, including biochemical no evidence of disease in 22% of patients. These findings also provide quantitative data on the delay of palliative hormone therapy initiation in the era of PSMA PET, which has not been shown before, of at least 1.5 years, based on their median time to PSA progression of 17.7 months. So this is important information when counseling our patients with regards to MDT in this clinical context.

Furthermore, the current study highlights and adds unique data that could help inform the management of these patients. So three points that the authors raised were, that using PSMA PET to both identify and guide treatment of oligorecurrent disease provides information on detection rates, patterns of recurrence, and clinical outcomes, and they mandated negative conventional imaging, which highlights the added value of advanced imaging to unveil the localized disease. They only included patients who had maximal local therapy and low PSA levels. And this investigation is at the earliest point of the non-curative spectrum for the current status quo, so really taking the imaging to the earliest of the people that have had a biochemical recurrence.

Several additional points regarding MDT trials to date. The main endpoints are limited to biochemical or disease response or progression and ADT survival, and different definitions among trials and initiation of salvage ADT lacks standardization. Secondly, all of these trials have used MDT alone without combined ADT or other systemic agents, and this is being investigated in several ongoing trials, including NRG GU011, STORM, the 1-STOP trial, DART, and also in RAVENS.

So in conclusion, data from this phase 2 trial provides evidence towards the ongoing debate of the existence of a curable oligorecurrent prostate cancer state, and it should inform the design of subsequent studies aiming to expand the therapeutic armamentarium for men with oligorecurrent prostate cancer deemed incurable by the current status quo treatment. For example, this should be discussed in exploring the role of combined androgen receptor-suppressing strategies with MDT. And finally, phase 3 RCTs are fundamental and must be supported in this disease space to conclusively determine the role at MDT and impact in clinically meaningful outcomes. Thank you very much for your attention. We hope you enjoyed this UroToday Journal Club.