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Christopher Wallis: Hello and thank you for joining us for this UroToday Journal Club. Today, we're discussing a recent publication looking at Lutetium-177-PSMA-617 in low-volume hormone-sensitive metastatic prostate cancer, as a prospective pilot study. I'm Chris Wallis a Fellow in Urologic Oncology at Vanderbilt. With me today is Zach Klassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. This is a citation for this recent publication in Clinical Cancer Research.

Metastatic hormone-sensitive prostate cancer is a relatively small subset of the disease in most of the western world. However, it is a relatively large proportion of the disease in other parts in the world. And in our country and in our regions, the rates of de novo metastatic hormone-sensitive diseases are rising and we see this as a result of changes in screening patterns and parts.

In the metastatic castrate-sensitive prostate cancer disease space, we've seen a real evolution in care in the last five years or so, beginning with CHAARTED, STAMPEDE and the GETUG trial, looking at docetaxel published in 2015 and 2016. We've now had subsequent three other agents that have been approved and now utilizing this disease space. All of these depend on a backbone of ongoing androgen deprivation therapy. However, the concept of oligometastasis suggests that there are patients who have a low volume of metastatic disease who are closer to those with localized disease and those with widespread metastases and as such, our conventional treatment paradigms with lifelong systemic therapy may not be the most appropriate choice. And so we've seen trials such as STOMP looking at the role of radiation to metastases in order to delay or prevent the use of systemic androgen deprivation. And rather than using external beam radiotherapy, the idea of theranostics brings in the potential to give targeted radiotherapy doses.

And so radiotherapy tracers can be used and PSMA is a well-known one. This is a transmembrane zinc metalloprotease, which is heavily overexpressed in prostate cancer. And we've used this for diagnostic imaging, but we can also use it for therapeutic purposes as a theranostic target. And so 177Lu-PSMA is a radionuclide that provides beta emission and this, as a result, has limited tissue penetration, decreases risk to adjacent organs. Additionally, lutetium is a low-level gamma-emitter, which allows for a concurrent imaging drug treatment. In addition to the details before, I like to highlight here that there are two different Lu-labeled radiotracers that are commonly used in PSMA theranostics, 177Lu-PSMA-617, 177Lu-PSMA, and PSMA-I&T. And in this study, we focused on an analysis utilizing the 617 form.

So in more advanced prostate cancer, we have a bunch of data that can guide you since this is the initial study from Dr. Hofman of the LuPSMA trial, as a single-arm study demonstrating relatively promising results in terms of PSA responses after the use of PSMA theranostics. And more recently, we've seen publications, a therapy trial, which provides randomized data among men with prior androgen ablation and docetaxel use. That the use of PSMA-based theranostics may be superior to second-line chemotherapy with cabazitaxel. So we see here a PSA reduction, which was their primary endpoint, but we also saw benefits and other secondary end-points as well in this trial.

And the present study, the authors sought to assess the toxicity, radiation doses, and treatment effect of using 177Lu-PSMA in patients with the low-volume metastatic hormone-sensitive disease, in contrast to these prior publications, which are focused on the castrate-resistant disease space.

To do so, they enrolled men age 50 years and older with histologically proven prostate cancer who had progressive disease following local therapy and they define this as a PSA greater than 0.2 ng/mL, a doubling time less than six months and no available curative treatment option. Patients had to have low-volume disease quantified as 1 to 10 sites of disease on 68Ga-PSMA PET/CT. In addition, patients could not have received ADT in the preceding three months, although a prior history of ADT use was allowed if this was used in the adjuvant setting with radiotherapy for localized disease. In addition, patients had to have normal kidney and bone marrow function and could not have visceral metastases.

This outlines the study procedures and if we go through it in sequence, we have the imaging here. So patients received PSMA-PET/CT in their workup in order to quantify the number of disease sites and ensure that eligibility for the trial. We then move into the treatment window and they received their first infusion of 177Lu-PSMA. This is graded by the second infusion by seven to nine weeks. One week prior to that second infusion, there's a repeat PSMA-PET/CT performed. After their second infusion, there's two subsequent follow-ups PSMA-PET/CT is performed, one at three months and one at six months following their second infusion. And notably, the first PSMA lutetium dose is standardized with the second dose adjusted on the basis of dosimetry and toxicity. Notably, dosimetry was performed radiographically using SPECT CT at 1, 24, 48, 72 and 168 hours following Lu-PSMA infusion. And then blood dosimetry was additionally performed at 5, 30, 60, 120 and 180 minutes, as well as 24, 48, 72 and 168 hours post-injection.

The primary endpoint was toxicity in this pilot study, but secondary endpoints included patient-reported quality of life, ADT-free survival, the best PSA response, as well as imaging response. The assessment was performed with weekly evaluation from the first dose through until 12 weeks after the second dose and then again, at the end of the study. Laboratory investigations were performed weekly and quality of life questionnaires were completed at baseline and every month until three months after the second dose and then again, at the end of the study.

As this was essentially an exploratory pilot study, there was not a formal sample size calculated. The dose calculations were performed using the Hermes Medical Solutions dosimetry software. This point in time, I'll pass it over to Doctor to walk us through the results of this pilot study.

Zachary Klassen: Thanks Chris, so this is the figure looking at the baseline characteristics of these 10 patients. You can see their age on the left, their Gleason score, primarily all high-risk disease, majority of four plus five equals nine, their PSA at the time of study entry, and then their injection dose schedule in the middle of the figure. And looking over at the right, we see the treatment broken down by color. And you can see, the first thing to point out on this figure, is that all these patients did have local therapy, primarily radical prostatectomy plus lymph node dissection. And as not to be unexpected, they all did receive Lu-PSMA as their final treatment. You can see in between, several patients had external beam radiotherapy as well.

This looks at the adverse events for these 10 patients. Most notably is that there was no Grade greater than equal to III attributed to the 177Lu-PSMA treatment. Looking at the Grade I-II most commonly was fatigued 70%, nausea 30%, xerostomia, which is often discussed when looking at Lu-PSMA, was 20%.

This looks at the quality of life based on the 10 patients in this study and, sort of, an overview highlight is that the majority of these patients did maintain a decent quality of life from baseline all the way through cycle two and month six of their treatment. There was five patients ahead of PSA response of greater than 50%, decrease in PSA during the follow-up time period. And you can see here that Patients 7 and 8 nearly had undetectable PSA. And you can see looking after the first cycle, a relatively rapid decrease in PSA for the majority of these patients. However, this figure looks at PSA response in patients with less than 50% decrease in PSA. And you can see that at the time of treatment, there really wasn't an increase or it really just wasn't that a decrease that the PSA value and what stayed relatively stable throughout the course of the follow-up.
This is the radiographic response for each of these patients. And you can see here from C1W8 to C2W12 to C2W24, there was a complete response in Patient 1 and then stable disease in Patient 3, partial response in Patients 5 and 6 and a partial response in Patients 8 and 9, with the remaining progressing over the course of follow-up.

So this figure looks at the PSMA PET before and six months after 177Lu-PSMA of the three best responding patients. And figures A, B, C, and D, you can see the correlating images of a perirectal lymph node in figure A that then disappears in figure B, in the corresponding images and C and D. Patient 2, E, F, G and H, there's a subcarinal lymph node, which subsequently disappears after treatment as you can see in figure F. And then finally in the third patient, I, J, K and L, there are several pelvic lymph nodes that then subsequently decrease in intensity after their treatment, as you can see in figure J.

So several discussion points for this study. This is the first study to evaluate the Lu-PSMA in low-volume metastatic hormone-sensitive prostate cancer and there was observed safety and tolerability in these 10 patients. Notably, there were no Grade III-IV treatment toxicity and only two patients reported mild xerostomia, which resolved within one month of their treatment.

The current study administered two cycles of 3 and 6 177Lu-PSMA with eight weeks in between, which is much lower than the standard protocol of four to six cycles of 7.4 per administration for those with advanced heavily pre-treated prostate cancer. After two cycles of Lu-PSMA therapy, the median ADT-free survival of all patients was 9.5 months. With 6 months, patients still deferring hormonal treatment at the time of the analysis.

So in conclusion, Lu-PSMA appeared to be feasible and a safe treatment option modality for these 10 patients with low-volume metastatic hormone-sensitive prostate cancer. And although the patients were treated with a relatively low dose of the Lu-PSMA, the majority of patients showed a promising response to this therapy. And certainly based on the size of this study, these results support the need for further trials and evaluation of the efficacy of Lu-PSMA in low-volume metastatic disease, as well as in hormone-sensitive prostate cancer in general.
Thank you very much for your attention and we hope you enjoyed this UroToday Journal club.