225Actinium PSMA-617 and 177Lutetium PSMA-617 Tandem Therapy in mCRPC Patients, Journal Club – Christopher Wallis & Zachary Klaassen

September 22, 2022

Christopher Wallis and Zachary Klaassen discuss a publication about 225Actinium PSMA-617 and 177Lutetium PSMA-617 tandem therapy in metastatic castration-resistant prostate cancer (mCRPC) patients who have previously been treated with 177Lutetium PSMA-617 monotherapy.


Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we're discussing a recent publication entitled Molecular imaging and biochemical response assessment after a single cycle of 225 Actinium PSMA-617 and 177 Lutetium PSMA-617 tandem therapy in mCRPC patients who have progressed on 177 Lutetium PSMA-617 monotherapy.
I'm Chris Wallace, Fellow in Urologic Oncology Vanderbilt. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. And this is the citation here for this recent publication in the journal theranostics. Theranostics by way of background is the combination of therapy and diagnostics, and so while there are a whole variety of permutations and iterations of the Theranostic approach, in prostate cancer we're predominantly focusing on targeted radiotherapy and radiotracers like PSMA are typically used to target this therapy.

PSMA itself is a transmembrane zinc metalloprotease. It's heavily over-expressed in prostate cancer cells. And as a result, has been utilized as a target for both diagnostic imaging and therapeutic purposes. There are a whole variety of PSMA-targeted Theranostics. The most common are beta-emitters, such as 177 Lutetium PSMA. It says relatively limited tissue penetration. And the two forms that are most commonly used are Lutetium PSMA-617 and the TCM PSMA-I&T. However, alpha-emitters can also be used as Theranostic therapy. And an example of this is 225 Actinium and alpha-emitters have a higher radiobiologic activity and effect. So maybe suitable where initial treatment with beta-emitters has failed. Lutetium PSMA is the treatment approach in this disease space that has the greatest data. And so this is the Lu-PSMA trial, single arm studies showing relatively promising PSA responses, which then led to the therapy trial as a randomized comparison of Lutetium PSMA and Cabazitaxel in patients who have previously received Docetaxel and Abiraterone or Enzalutamide.

And this study showed a relatively promising PSA responses with a [inaudible 00:02:29] significant benefit to the use of a Lutetium PSMA as compared to second-line chemotherapy. In this study, the authors undertook a retrospective single-center analysis of patients who received a salvage cycle of Actinium and Lutetium PSMA tandem therapy, after failure of prior Lutetium PSMA Theranostic treatment. They included men with prior mCRPC who had, had at least two cycles of 177 Lutetium PSMA-617 monotherapy.

Following this treatment, they defined progression as a PSA increase of at least 25% or increased uptake or new metastases according to radiographic imaging with 68 Gallium-PSMA. The PSMA based imaging had to be performed within one month prior, as well as following tandem therapy. In addition, there had to be a biochemical coordinates of a PSMA and FDG PET-CT results with evidence of PSMA avidity as with most of these types of studies that had to be hematologic and renal function which was adequate for treatment as well as a performance status of 0-2.

This highlights the protocol following an initial, a minimum of two cycles of Lutetium PSMA. Patients who had progression were offered one cycle of tandem therapy. And again, as we can see below here, they had imaging and biochemical testing prior to this cycle and subsequent, and the analysis of this study focuses on both a molecular imaging response, as well as a biochemical response. Here we see the characteristics of the 17 included patients. Mean PSMA cycles prior to this salvage attendance cycle is five cycles of Lutetium PSMA. The median start from the time of their initial Theranostic therapy to the start of this tandem salvage cycle was 40 weeks. Most said fairly significant increases in PSA of almost 300%.

In terms of the mechanism of tandem therapy, both radioligands were administered simultaneously during an inpatient stay. And you can see the mean administered activity here. Other treatments including androgen deprivation, Abiraterone, and Enzalutamide, or continued on an individualized basis. And it's worth noting that the Theranostic doses of Actinium and Lutetium were chosen on the basis of patient and disease characteristics.

And so for example, those who had a relatively high tumor burden or lack of response to their initial at 177 Lutetium monotherapy received a higher Actinium dose. Whereas those who had a lower tumor burden or unfavorable patient characteristics received a lower dose, and as a result, the lower Actinium to Lutetium ratio. In terms of evaluation, imaging was performed with a 68 Gallium-PSMA PET-CT. This was performed approximately one week, five days to one week prior to tandem therapy. And then subsequently about seven weeks after tandem therapy.
Radiographic responses were assessed by collecting two metrics; one, the whole body total lesion PSMA, the TLP, as well as the molecular tumor volume, the MTV. And these were calculated on a basis of the comparison of the pre-treatment and post-treatment PSMA PET-CT scans. And the authors, you semi-automated tumor segmentation with an SUV threshold of three to identify the tumor volume.

They used a PERCIST criteria to define partial remission, stable disease, and progressive disease according to these radiographic responses. And additionally assessed about chemical responses using the prostate cancer working group three definition of partial stable and progressive disease. This point in time, I'll pass it over to Zach to take us through the remainder of this paper.

Zachary Klaassen: 
Thanks Chris. So this looks at a representative example of semi-automatic tumor segmentation using the platform on the left is maximum intensity projection of Gallium PSMA-11. In the middle is a sagittal slice of the PET-CT fusion. And on the right is the PET data with a semi-automatically drawn volumes of interest noted in green here. In terms of statistical analysis, the authors use descriptive analysis and concordance assessment of molecular imaging and PSA responses. And there was association between baseline characteristics and response tested with Spearman's correlation, and overall survival was assessed in a startup tandem therapy to any cause of death, the start of next treatment including chemotherapy or censoring at the last clinic visit.

Looking at the results, this shows the absolute values of TLP, MTV, and PSA prior to, and after tandem therapy. And so on the left here, as you can see with my cursor, this is a TLP prior to therapy and after therapy. You can see prior to therapy, there was a large range in TLP ranging from 723 mL x SUV up to 13,679. And you can see here, a number of these patients had a significant decrease. Patient 2 from 13,679 to 5,113, patient 8, 4,282 down to 726.

Similarly, in terms of MTV prior and after therapy in the middle of this table, you can see another wide range ranging from 187 to 1,263. And once again similarly, patients had a substantial decrease in some of these cases. Patient 2, 2,581 down 1184. And you can also see that there was some increases we'll go over in the next slides, such as patient 7, going from 1263 up to 4,542. And finally on the right PSA prior to therapy, a wide range again from 5.9 in Patient 17 up to 2,570 in Patient 11, with a corresponding, some of these patients having a great PSA response such as this patient. Patient 2 going from 1,277 to 367, whereas otherwise patients also increasing in their PSA such as Patient 7, going from 103 to 750.

This table looks at the changes in TLP, MTV, and PSA, and the respective responses on the ah, summarize this on the right here, you can see TLP and MTV. Both of these had a five out of 17 patients with partial response. Seven out of 17 had stable disease and five out of 17 had a progressive disease in comparison by PSA evaluation, five patients with a partial response, eight with stable disease and four with progressive disease. We're looking at concordance between TLP and MTV. This was a hundred percent and we're looking at TLP and MTV compared to PSA. This was a 70.6% concordance right. These are waterfall plots basically summarize the previous slide, showing the change in TLP on the left, the change in MTV in the middle and the change in PSA on the right.

This table looks at the correlation between pre-therapeutic parameters and changes in TLP, MTV, and PSA. You can see a number of these parameters on the left here in terms of prior PSA, part of tandem therapy, the administered 225 Actinium activity, and so on all the way down to PFS after chemotherapy in 13 out of 17 patients. And to summarize this table, all of these parameters on the left had a non-significant P-value when correlated with change in TLP, change in MTV or change in PSA.

This looks at the adverse events before and after a single cycle of tandem therapy. The before tandem therapy is on the left, and the after a single cycle of tandem therapy is on the right, which will focus on here. Importantly, there was no grade four adverse events in any of these patients. There was one patient that had a grade three event which was thrombocytopenia. Otherwise, this was relatively well tolerated in terms of grade three and four adverse events.

This is an example of concordance between molecular imaging response assessment and biochemical response assessment in terms of a partial remission in patient 8. On the left, you can see here, the TLP was 4,282. The MTV was 588 and the PSA was 123. The patient then received the tandem therapy. And then you can see a nice reduction in all three of these parameters with TLP reducing to 726 MTV down to 171 and PSA down to seven.

This is the Kaplan-Meier curves for overall survival stratified by molecular imaging response and biochemical response assessment. And this is actually probably the most important results slide of this talk, in that the overall survival, when looking at the molecular imaging response was significantly different between a partial response and those with stable or progressive disease, as you can see here by the splitting of the Kaplan-Meier curve and the significant P-value of 0.044. Looking at the biochemical response, this was a non-significant assessment between partial response and stable or progressive disease with a P-value of 0.468.

So several discussion points from this study. This is the first study investigating molecular imaging and biochemical response assessments after a single cycle of Actinium PSMA and Lu-PSMA tandem therapy in patients with mCRPC who had progressed on prior Lu-PSMA monotherapy. The study showed that five of 17 patients or 29.4% had a partial remission. The Gallium PSMA-11 derived parameters, TLP and MTV, which are molecular parameters and PSA response should be considered independent response assessment methods. And finally, in this discussion session, a single cycle of Actinium PSMA and Lu-PSMA tandem therapy was safe in this study with only one patient having a grade three, four adverse event, which was thrombocytopenia as previously discussed.

So in conclusion, 225 Actinium PSMA and Lu-PSMA tandem therapy is an effective treatment for the highly challenging cohort of patients with mCRPC who have progressed on Lu-PSMA monotherapy. Molecular imaging response based on Gallium PSMA-11 PET-CT derived parameters, such as TLP and MTV and PSA response were mostly concordant. However, there was discordance in 29% of these cases. Molecular imaging response reflecting the change in viable total tumor burden appears to be superior to PSA change and estimating survival outcomes after tandem therapy. And finally larger and ideally prospective studies are recommended to confirm and expand on these findings. Thank you very much. We hope you enjoyed this URO Today Journal Club discussing tandem therapy after Lutetium monotherapy failure.