Chris Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today we're talking about a recent paper entitled Safety and Survival Outcomes of Lutetium-177 Prostate-Specific Membrane Antigen Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer with Prior Radium-223 Therapy: the RALU Trial. I'm Chris Wallis, an assistant professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia.

You can see here, this citation for this recent publication in the Journal of Nuclear Medicine that was published online as of October 27th, and it's clearly late breaking work.

The mCRPC space, as most will know, has evolved relatively rapidly. Our first life-prolonging agent was approved only in 2004 with Docetaxel, based on the results of the TAX 327 trial, and since that time, we've had many approvals. However, survival for these patients remains relatively poor, and so novel treatment paradigms are still needed. The most recently approved approach here is the use of Lutetium-177 PSMA.

However, we have historic data from the ALSYMPCA trial demonstrating the utility of Radium-223. This is a targeted alpha therapy, which, as you can see in the highlighted figure on the right, specifically targets bone-related prostate cancer metastases. It has a good safety profile, and in the ALSYMPCA trial demonstrated both improved overall survival, as well as improved quality of life in patients with bone-predominate mCRPC. There's notably relatively low rates of myelosuppression with the radium.

As I alluded to in the flow diagram, Lutetium-177-PSMA-617 is sort of the new kid on the block here. The results of the VISION Trial were presented and published in the last a year and a half or so, and we see really that the beta-emitter in Lutetium-177, the target's not based on bone tropism, but PSMA expressing cells, and in the VISION Trial, the use of Lutetium-177 was associated with improved overall survival, as well as acceptable safety in patients who are heavily pretreated. Other PSMA-based radioligands, including 177-Lutetium-PSMA I and T, have demonstrated promise and are being evaluated in ongoing trials.

The question, therefore, is what do we do in terms of combination and sequencing of therapies? Both of these agents are approved for mCRPC, although in somewhat different patient populations, and so these authors sought to assess the safety and survival outcomes of patients who received a sequence of Radium-223 followed by Lutetium-177. Prior retrospective data have suggested that this approach may be both safe and feasible.

So, this was a multi-centered medical chart review among patients with mCRPC treated in Germany. They had to be age 18 years and older and have received at least one cycle of Radium-223, and at least one cycle of Lutetium-PSMA.

As you can see in the highlighted figure on the right, the authors first began their observation period at the time of mCRPC diagnosis, and continue this through to either the last available visit for patients who are still alive, or death. They define pre-baseline treatment and follow up periods, as you can see in this figure, with the Lutetium-PSMA being the key exposure time distinguishing treatment, and Radium occurring in the pre-baseline period.

So, the primary endpoint was the safety of 177-Lutetium-PSMA following Radium-223 therapy. This was defined on the basis of adverse events and grade three or four laboratory abnormalities. Secondarily, the authors considered overall survival, time to next treatment, change from baseline in serum PSMA, and change from baseline in serum alk phosphatase.

Now I'm going to hand it over to Zach to walk us through the results of the RALU study.

Zach Klaassen: Thanks so much, Chris, for that great introduction. This is the baseline characteristics of the patients in this study before starting Lutetium-PSMA. We can see, as Chris mentioned, there was 49 patients included, with a median age of 72 years. Given the high treatment burden beforehand, the ECOG performance status was quite good, with 73% of patients having an ECOG one and 27 with an ECOG two. The median PSA, as expected, was high at 287, with a high median alk phos of 142.5.

In terms of patients that had visceral metastases, 31%. Impressively, 61% of patients had four or more life-prolonging therapies prior to inclusion in this study. In terms of novel antiandrogen therapies, 80% of patients had previous Abiraterone. 67% had prior Enzalutamide. In terms of number of taxing-based chemotherapy lines, 20% had two or more lines of therapy. In terms of Docetaxel, 53% had five or more cycles of Docetaxel, and 10% of patients had five or more cycles of Cabazitaxel. Interestingly, taxane-based chemotherapy between the time of radium and Lutetium-PSMA was roughly half of the patients.

This figure looks at the use of life-prolonging therapies. On the left we see that from mCRPC diagnosis to the start of Lutetium-PSMA, 100% of patients had Radium-223, 92% of patients had Docetaxel, 80% of patients with Abiraterone, and 67% of patients had Enzalutamide, and 18% of patients had Cabazitaxel. In the middle, in terms of during the Lutetium-PSMA treatment, there was 18% of patients that still were on Enzalutamide at that time, and 10% on Abiraterone concurrently with Lutetium-PSMA therapy. In terms of after Lutetium-PSMA therapy, 14% of patients were receiving Abiraterone and 14% receiving Enzalutamide, as well as 6% of patients receiving Cabazitaxel and 6% receiving Docetaxel.

This table looks at the incidence of grade three and four abnormalities from the time of Lutetium-PSMA to 90 days after the last dose, and you can see that this is relatively well tolerated. Roughly one-third of patients, 35%, had anemia. 13% had thrombocytopenia. 2% had neutropenia, and 4% had abnormalities in their liver function tests.

This Kaplan-Meier plot looks at overall survival calculated from the first dose of Lutetium-PSMA, and you can see here that the median overall survival with these metrics was 12.6 months with a 95% confidence interval of 8.8 to 16.1 months.

This is the overall survival calculated from the first dose of Radium-223, over 2.5 years, so 31.4 month, median overall survival, the 95% confidence interval of 25.7 to 37.6.

This is a nice graphical abstract provided by the authors for this study, and again, highlighting that the rate of grade three to four treatment emergent adverse events was 41%. Again, highlighting that the overall survival from the first dose of Lutetium-PSMA, median overall survival was 12.6, and from the first dose of Radium-223, median overall survival of 31.4 months.

So, in this study, Lutetium-PSMA following Radium-223 treatment had an acceptable safety profile, and this is despite the patient population being heavily pretreated, with over 90% of patients having received chemotherapy in addition to Radium-223 and Lutetium-PSMA.

The median overall survival from starting Lutetium-PSMA or Radium-223 therapy was 12.6 and 31.4 months respectively, which does correspond to those reported in the REASSURE Trial, which was 13.2 months and 28 months respectively. Finally, the WARMTH study. For patients receiving Lutetium-PSMA, overall survival was longer in those patients with bone metastases receiving prior Radium-223 versus those who did not.

So, in conclusion, this retrospective cohort study demonstrates that for patients with bone-predominant mCRPC receiving radium-223 in routine care, subsequent Lutetium-PSMA was clinically feasible, as well as well-tolerated, with limited rates of myelosuppression. As highlighted in the discussion, survival outcomes reflected those from previous reports. Therefore, in patients with bone-predominant mCRPC, Radium-223 use before Lutetium-PSMA can be considered in future assessments of optimal treatment sequencing of life-prolonging therapies.

We thank you very much for your attention. We hope you enjoy the UroToday Journal Club discussion of the RALU study.