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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, which is a protocol rather than the results of an analysis, which differs a bit from our usual UroToday Journal Clubs. However, we thought this was a particularly interesting and timely topic and wanted to bring it to your attention. The paper in question is entitled, UpFrontPSMA: A randomized phase 2 study of sequential 177Lu-PSMA-617 and docetaxel versus docetaxel in metastatic hormone-naive prostate cancer, a clinical trial protocol. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt. With me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. This is the citation for this recent protocol publication, which was published in BJU International.

Metastatic hormone-naive prostate cancer or de novo metastatic prostate cancer is relatively uncommon in the United States and in most of the Western world, accounting for between 3% and 5% of new cancer diagnoses. However, it is substantially more common in other parts of the world and with changes in screening recommendations in the United States, is becoming more common in the last few years. In the last five years, we've seen a number of new agents approved by the FDA in this disease space. Beginning in 2015 and 2016, where docetaxel showed evidence of benefit in level one trials, we saw its utilization, although this did not require a new approval. Subsequent to this data from LATITUDE and STAMPEDE, they supported the use of abiraterone followed by enzalutamide and apalutamide in the coming year.

More recently with a focus primarily on diagnostic, we've seen the development of PSMA-based approaches. PSMA is a transmembrane zinc metalloprotease. It is heavily over-expressed in prostate cancer and actually moves within the gland in the disease state. It has been targeted both for diagnostic imaging, but more recently also therapeutic purposes in a theranostic setting. 177Lu-PSMA is used as a radionuclide. This is a beta-emitter, which has limited tissue penetration, preventing toxicity on surrounding tissues, as well as low-level gamma emissions, which allow for concomitant imaging.

177Lu-PSMA has been used as a theranostic and there are two commonly examined radiotracers so far, 177Lu-PSMA-617 and 177Lu-PSMA-I&T. In the setting of metastatic castration-resistant prostate cancer, we have two trials. The first one is the Lu-PSMA trial, which was a single-center, single-arm, phase two study. As you can see here, it shows relatively good PSA responses for patients who are heavily pretreated. Following this, we had the TheraP trial. This was a randomized, open-label, phase two trial again in the metastatic castration-resistant prostate cancer setting for patients who had previously received docetaxel and were being considered for cabazitaxel. As you can see looking at the primary endpoint of PSA, a reduction from baseline. PSA responses are significantly more common in patients who received 177Lu-PSMA as compared to those who received cabazitaxel.

So the hypothesis of the UpFrontPSMA trial is that the addition of 177Lu-PSMA-617 to androgen deprivation therapy followed by docetaxel will result in a greater proportion of patients with metastatic hormone-sensitive prostate cancer achieving an undetectable PSA compared to ADT and docetaxel alone.

In broad terms, this is a multi-center, open-label randomized, stratified two-arm phase two trial enrolling patients with de novo metastatic hormone-sensitive prostate cancer who are deemed suitable for docetaxel with 1:1 randomization to 177Lu-PSMA plus docetaxel plus ADT versus docetaxel and ADT alone. And randomization is stratified based on the disease volume as well as the lead in duration of ADT.

The primary endpoint of this study is the proportion of men who have an undetectable PSA defined as less than 0.2 ng/mL at 12 months following protocol commencement. And the authors are also planning to assess a number of secondary endpoints, including safety, time to castration resistance, PSA and radiographic progression-free survival, tumor responses, as well as the effect of imaging response rates, patient-reported outcomes, and finally, overall survival.

In somewhat more detail, there are two levels of inclusion and exclusion criteria. First, there are the registration characteristics. This includes adult men with prostate cancer diagnosed within the last 12 weeks who have a histologically or pathologically confirmed diagnosis of adenocarcinoma. On conventional imaging, the patients have to have metastatic disease and PSA must be at least 10 ng/mL prior to the initiation of ADT. In addition, they must have adequate organ function, decent performance status, a life expectancy of at least six months, and be assessed by medical oncologists who feel that they are suitable for docetaxel. Notably, patients with prior prostate cancer treatments are excluded except for the allowance for four weeks of androgen deprivation therapy and after one course of palliative local therapy, including radiation or surgery. Further, patients were excluded if they have symptomatic cord compression, CNS metastasis, Sjogren's syndrome, or a history of other cancers.

Following this initial registration phase, there is a subsequent randomization inclusion and exclusion based on the results of imaging studies. To be included, patients had to have significant PSMA avidity, at least one site with a central review demonstrating SUVmax of at least 15. Further, based on their PSMA PET/CT, they had to have high volume disease to find visceral metastases or more than four bone metastases with at least one extra-axial metastasis. Notably, patients are excluded if there is major FDG-PET discordance when there is FDG positive disease that lacks PSMA avidity.

This highlights the study schema again, emphasizing the overall registration eligibility followed by imaging using PSMA PET/CT and FDG PET/CT. This is then followed by randomization to 177Lu-PSMA-617 followed by docetaxel or docetaxel alone. Again, this randomization stratified by disease volume and duration of ADT, and all patients receive continuous ADT.

At this point in time, I will hand it over to Zach to take us through a few more details of how the authors plan to conduct this study.

Zachary Klaassen: Thanks Chris. So they looked at a section in the trial protocol of dose delays and modifications, and they noted that, as Chris mentioned, there will be two cycles. However, the dose of 177Lu-PSMA for cycle two will be reduced by 20% for participants of dose-modification toxicity following cycle one. Importantly, they also note that dosing of Lu-PSMA can also be delayed for a maximum of four weeks. However, if Lu-PSMA is discontinued, patients should still proceed with docetaxel treatment if they are randomized to that appropriate arm.

In terms of treatment discontinuation, they list several reasons for discontinuation including unacceptable toxicity, unequivocal disease progression, which they define as radiographic progression and/or symptomatic progression, intercurrent illness preventing further treatment, withdrawal of consent from the trial, treatment no longer in the patient's best interest as deemed by the investigator, and patients with significant protocol non-compliance. Patients with progression during or after Lu-PSMA treatment will still proceed with docetaxel therapy.

This looks at the schedule of assessments for Arm A, which is Lu-PSMA plus docetaxel. On the left of this figure, you can see the windows/assessment in terms of clinical assessment, imaging, as well as biomarker collection. The first part of this table is a screening portion of the trial followed by the treatment phase for this arm, which includes Lu-PSMA cycles one and two, followed by six cycles of docetaxel. On the right, we see the follow-up including the safety follow-up, follow-up thereafter, and then just survival follow-up. So there is a number of clinical assessments that are going to be obtained in the screening phase, as well as with each treatment phase and follow-up.

Moving down here to the middle of the figure, they are going to obtain a PSMA PET scan at the time of screening, and then 12 weeks plus or minus seven days from cycle one, day one of Lu-PSMA treatment, and prior to commencement of docetaxel. They will also complete an FDG PET/CT scan at the time of screening, and then subsequently at 12 weeks plus or minus seven days from cycle one, day one of Lu-PSMA treatment, and prior to commencement of docetaxel if there is an FDG avid disease at the baseline screening study.

This is a schedule of assessments for Arm B, which is the docetaxel arm. It looks very similar to Arm A. Of course, the treatment phase just includes docetaxel cycles one to six. Similarly, they will obtain a PSMA PET and FDG PET at the screening visit, and then subsequently at 12 weeks plus or minus seven days from cycle one, day one of docetaxel and prior to the next cycle of docetaxel.

In terms of statistical considerations, the primary endpoint for UpFrontPSMA is undetectable PSA at 12 months after initiation of protocol therapy. Looking at the CHAARTED data, 27% of all metastatic hormone-sensitive cancer patients treated with ADT plus docetaxel attained a PSA less than 0.2 ng/mL at 12 months. This is assuming that 25% of patients in Arm B will have a PSA of less than 0.2 at 12 months. With 140 patients randomized 1:1 between these two treatment arms, the study will have an 85% power to reject the null hypothesis that the 12-month undetectable PSA rate in Arm A is 50%. This power calculation also assumes that no more than 7% of 140 patients will be unevaluable or lost to follow-up in the one year during the assessment phase.

So several discussion points from this clinical trial protocol of the UpFrontPSMA study. Although there has been a major shift in the treatment paradigm for patients with metastatic hormone-sensitive prostate cancer, the outcomes for those with de novo high-volume disease still remain poor despite all of the treatment options Chris mentioned earlier in the presentation. UpFrontPSMA will be the first multicenter, prospective, randomized trial evaluating 177Lu-PSMA followed by docetaxel versus docetaxel alone in newly diagnosed metastatic hormone-sensitive prostate cancer patients with high volume disease on PSMA PET. The authors also discussed several reasons behind the number of cycles and timing of Lu-PSMA. So in terms of the reason between Lu-PSMA followed by docetaxel, their reasoning was that the Lu-PSMA treatment will debulk large tumor volume with smaller deposits being treated by the subsequent docetaxel. In terms of limiting to two cycles of Lu-PSMA, this was discussed with regards to preventing undue delay of docetaxel treatment, which we all know is a standard of care treatment for these patients.

In conclusion, this study is open for enrollment, has been open for a year, first recruiting patients on April 17, 2020. UpFrontPSMA will improve our understanding of 177Lu-PSMA activity and safety in men with de novo metastatic hormone-sensitive prostate cancer and shape the design of phase three trials in this important disease space. Anticipating the early use of Lu-PSMA as a first-line sequential treatment will lead to improved outcomes with minimal toxicity. Importantly, this trial will also provide novel explorative data in the evolving field of molecular imaging biomarkers.

Thank you very much. And we hope you enjoyed this discussion of the UpFrontPSMA clinical trial protocol, and we are looking forward to hopefully discussing these results of the trial in the near future.