Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're talking about a recent publication entitled, mCRPC patients receiving 225 Actinium-PSMA-617 therapy in the post androgen deprivation therapy setting: Response to treatment and survival analysis. I'm Chris Wallis, and assistant professor in the Division of Urology at the University of Toronto, with me today is that Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. You can see here, the citation for this recent publication in the Journal of Nuclear Medicine.

Most people listening to UroToday will know that prostate cancer is the second most frequent cancer in men worldwide and contributes significantly to the overall burden of prostate cancer and overall cancer mortality in men. While survival is hard for men with localized prostate cancer, it's remained relatively poor for those with metastatic disease. For over 50 years now, androgen deprivation therapy has been the standard of care. However, in the last decade or so, treatment intensification has been identified as beneficial in men with metastatic prostate cancer, beginning in the mCRPC setting and moving now to mCSPC. Nearly all patients who have metastatic disease receiving ADT alone will progress to castration resistance after a mean of between 1.5 to 3 years.

In low and middle income countries, the treatment of prostate cancer is somewhat complicated due to a relatively advanced presentation for many patients due to a lack of regular PSA screening, as well as issues with access to systemic therapy, many patients in these countries, as the authors here report, decline ADT or chemotherapy due to a fear of the toxicity, and newer agents, including abiraterone and enzalutamide, are not accessible.

Radioligand therapy is an alternative treatment approach, and 225 Actinium has been shown to be effective in patients with heavily pretreated mCRPC. In dose de-escalation studies has been found to be well tolerated, with the most prevalent toxicity being grade 1 or 2 xerostomia, making it a potentially more acceptable treatment option for patients.

The goal of this analysis is therefore to report treatment outcomes of 225 Actinium-PSMA-617 in patients with mCRPC who receive this therapy immediately following ADT. To do so, the authors performed a retrospective cohort study among patients who were diagnosed either with localized, or initially metastatic disease, but who presented with metastatic disease. To trigger treatment with 225 Actinium, patients had to have evidence of progressive disease on ADT, with a minimum of two rising PSA values with at least 1 week in between them. The decision to treat was made in a multidisciplinary setting, and all patients were aware that this approach has not yet received regulatory approval. Patients were included if they had metastatic disease, precluding local therapy, refused chemotherapy, and did not have access to second generation anti-androgens. Patients were excluded if they had urinary tract obstruction or bone marrow suppression defined as CTC grade 3 or greater.

All patients underwent an initial 68 Gallium-PSMA-11 PET/CT, and had to have identified PSMA-avid lesions with uptake greater than normal liver parenchyma. Patients then underwent laboratory investigations, both at baseline and prior to each subsequent cycle to ensure they were eligible for radioligand therapy. The 68 PSMA-11 PET/CT was performed after each cycle to guide dose de-escalation. Treatment was initially administered at 8 MBq for all patients, and subsequent doses were deescalated based on the response as evaluated using the 68 Gallium-PSMA PET/CT. Treatment was repeated every 8 weeks, provided there was continued response, no dose-limiting toxicity, and evidence of residual PSMA-avid tumor on the Gallium-PSMA. Patients were monitored for a minimum of 4 hours after treatment for acute toxicities and received blood work prior to each cycle to ensure they remained eligible. After the completion of all cycles, blood work was repeated every 12 weeks and patients with evidence of toxicity were followed until resolution or death. Toxicity was assessed according to CTCAE version 5 criteria.

Treatment response was evaluated using both PSMA imaging and PSA metrics. The 68 Gallium-PSMA was reported every 8 weeks prior to each treatment cycle, then subsequently every 12 weeks thereafter following treatment completion until either a progression or death. The PSA response was assessed as a PSA50 with a greater than 50% decline. PSMA-based imaging criteria were also used to assess response, with patients divided into those with complete response, partial response, stable disease, and those with progressive disease or non-responders. Progression-free and overall survival were estimated in Kaplan-Meier method and the authors use log rank tests to assess the association between a number of baseline characteristics with survival. Cox proportional hazards models were subsequently built to examine the predictive value of these variables using univariable p-value screening for model building.

I'm going to hand it over to Zach, at this point, to walk us through the results of this analysis.

Zachary Klaassen: Thanks so much, Chris. This is the table one patient characteristics. As mentioned, there was 53 patients included, with a median age of 63.4 years, and 42 of these 53 patients having an ECOG score of 0 or 1. Not surprisingly, there was a high median PSA in this cohort of 466, median alk phos of 188, and median hemoglobin of 11.5. Bone metastases was seen in the majority of these patients, 47 out of 53, lymph node metastases in 36 patients, and visceral metastases in 6 patients, most commonly in the liver. With regards to local therapy, 31 patients had a prior prostatectomy, 11 had prior radiation therapy, and 11 did not have prior local therapy.

In terms of toxicity profiles of the patients treated with Actinium-PSMA-617, you could see, most commonly, was xerostomia, 81% of patients having grade 1 or 2, but no grade 3 or grade 4 events for xerostomia. Anemia, 13% of patients grade 1 or 2, leukopenia, 7% of patients grade 1 or 2, and thrombocytopenia, 9% of patients grade 1 or 2. With regards to renal failure, 13% of patients had grade 1 to 2 events and 2 patients had grade 3 and 1 patient had a grade 4 renal failure event.

This is the waterfall plot looking at percentage change in PSA levels after treatment with Actinium-PSMA-617. This is quite an impressive waterfall plot, as you can see on the left, with a PSA decline of greater than or equal to 50% in 91% of patients and any PSA decline in 96% of patients.

This table looks at univariable analysis of the relationship between variables for progression and overall survival. Looking at the statistically significant variables for progression free survival. We see that this included PSA decline of more than 50%, an undetectable PSA, platelet count, radiological response, and a negative PSMA PET/CT scan. With regards to overall survival, the only significant variable was PSA greater than our equal to 50% decline.

These are the Kaplan-Meier curves provided in this paper, and I apologize for the poor resolution in the publication, but we can see here, starting on the left, this was PSA based overall survival with responders in green and non-responders in blue. The median overall survival for responders was not reached and the median overall survival for non-responders was 9 months. In the middle. We can see PSA-based progression-free survival. For responders, median progression-free survival was 22 months and for non-responders it was 4 months. On the far right is the analysis of progression free survival by platelet count, and you can see here that patients with a high platelet count, more than 293,000, in green, had a worse progression-free survival compared to those in the low platelet count in blue.

Several important discussion points from this study. In this series, 91% of patients with mCRPC had a greater than or equal to 50% PSA reduction following Actinium-PSMA-617 treatment. Importantly, this exceeds the PSA reduction seen with abiraterone, which was roughly 30% greater than or equal to 50% PSA reduction, cabazitaxel roughly 40%, and enzalutamide approximately 50%. This suggests that radiation resistance to alpha emitting agents following ADT is not an issue, which may be an issue for beta emitting agents, such as Lu-PSMA, that has reported response rates of roughly 10-69%. A PSA decline of greater than equal to 50%, as recommended by the Prostate Cancer Working Group, was the single most important factor predicting progression-free survival and overall survival following Actinium-PSMA-617 treatment. Finally, a high platelet count was associated with worse progression-free survival, and this may be secondary to platelets interacting with tumor and endothelial cells, thus potentially enabling metastases. This also may be due to the platelet shielding tumor cells from immune elimination.

In conclusion, among patients with mCRPC, receipt of Actinium-PSMA-617 resulted in a greater than 50% decrease in PSA level in 91% of patients. A PSA decline of greater than or equal to 50% was also the most important factor predicting PFS and OS following Actinium-PSMA-617. Finally, Actinium-PSMA-617 is a highly promising option for therapy of mCRPC directly following ADT and warrants further study in randomized trials. We thank you very much for your attention, and we hope you enjoyed this UroToday Journal Club Discussion.