Long Term Use of Lutetium-177-PSMA Therapy for Men With Metastatic Castration-Resistant Prostate Cancer, Journal Club – Christopher Wallis & Zachary Klaassen

September 20, 2021

In this UroToday Journal Club between Christopher Wallis and Zachary Klaassen, discuss the publication titled “Lutetium-177-PSMA Therapy for Men with Advanced Prostate Cancer: 18 Months Survival Analysis in a Single Australian Tertiary Institution”. This Journal Club kicks off with a background, and evolution, of metastatic castration-resistant prostate cancer (mCRPC). Dr. Wallis then goes on to discuss the background of the study. Dr. Klaassen discusses the results of the study. Dr. Klaassen explains the 18-month overall survival data in conjunction with different PSA responses. This Journal Club concludes with a synopsis of the findings from this study and a brief discussion on Lutetium-177-PSMA studies going forward.

Biographies:

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 are discussing a recent publication entitled, Lutetium-177-PSMA therapy for men with advanced prostate cancer: 18 months survival analysis in a single Australian tertiary institution. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt and 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 publication.

And like most people who follow UroToday will know, the disease space in metastatic CRPC has rapidly evolved over the last 10 or 15 years and we have had the introduction of a whole variety of new therapies, including a number of cytotoxic options, androgen receptor targeting agents, as well as immunotherapy and most recently PARP inhibitors. However, apart from radium-223, we haven't seen advances in radionuclide therapy.

And so this is the ALSYMPCA trial, which formed the basis of the approval of the alpha emitter, radium-223. As you can see, it was patients with confirmed metastatic castration-resistant prostate cancer, who are either post-docetaxel chemotherapy or ineligible for chemotherapy. They were randomized in a two-to-one fashion to radium or placebo.

And what we see here is not just improvement in symptoms, as we saw with early radionuclide therapy, but also an improvement in overall survival.

However, those efforts to improve the radionuclide approach we used, as radium-223 rely on being a calcium emetic and we may more accurately target prostate cancer cells. And so one of the ways to do this is the use of PSMA. This is a transmembrane zinc metalloprotease, which is heavily over-expressed in prostate cancer, and may allow for both diagnostic and therapeutic targeting. And so lutetium-PSMA is a radionuclide with low-level beta emission that has limited tissue penetration, decreasing its effect on adjacent normal tissues, and also has a low level of gamma emission, which allows for imaging at the time of treatment.

And so lutetium-PSMA has been established in mCRPC on the basis of the single-arm Lu-PSMA trial which demonstrated improvements in PSA outcomes. And subsequently, this led to the TheraP trial, which is a randomized comparison against cabazitaxel in patients who had progressed on docetaxel. And again, we saw improvements in PSA-based metrics. However, these data are limited by the duration of follow-up and as well as the lack of focus on important clinical outcomes, including overall survival.

And so in this study that we are discussing today, we're looking at the long-term survival of patients who are treated with lutetium-PSMA for mCRPC in a single Australian institution. And this study included men with heavily pretreated mCRPC and shortly Zach will walk through the degree of prior treatment these patients received. All patients underwent a multidisciplinary assessment for eligibility and this included gallium PSMA PET/CT, as well as hematologic, LFT, and electrolyte testing. Patients who were included were treated between August 2017 and August 2019 to allow sufficient follow-up. Treatment was administered over every six weeks in three to six cycles per patient and they could also receive concurrent therapy with other standards of care, including radiotherapy, but they did not receive concurrent chemotherapy.

As part of their ongoing monitoring of patient-centered care, the authors had assembled a theranostic database, which included details regarding prostate cancer history, prior treatments based on clinical characteristics, baseline imaging characteristics, the lutetium-PSMA treatment details, and follow-up details. And so for the purpose of this report, the primary outcome was overall survival and analytically they used the Kaplan Meier technique and then the log-rank test to test for differences in overall survival on the basis of both baseline characteristics and biochemical response.

Now I will hand it over to Zach to walk us through the results of this.

Zachary Klaassen: Thanks, Chris. This is a summary of the baseline characteristics of this study. There were 68 patients with a mean age of 71 years, a median number of Lu-PSMA cycles of three, a median PSA of 37.5, and a median SUV max of 19.7.

This table looks at the serum PSA level and SUV max of target lesions at baseline. And on the left, you will see metastasis location and we will focus on the median values for these locations. So in terms of baseline serum PSA, the median PSA for lymph node-only disease was 18, for bone-only disease was 66, for lymph node and bone disease was 81, and for visceral metastasis 27.5. Similarly, if we look at the median baseline SUV max values by location, for lymph node only disease was 24, for bone-only disease was 18.5, for lymph node and bone disease was 21.5 and for the visceral disease was 15.2.

This is the Kaplan-Meier estimate of 18-month overall survival. You can see the curve here, and the 12-month OS rate was 75% and the 18-month overall survival rate was 64%.

This looks at the 18-month OS estimate group by baseline serum PSA level. The orange line, which you can see here, PSA less than 20 with a 79.9% 18-month OS rate, and the blue line with PSA greater than 20, a 53.8% 18-month OS rate.

This looks at the breakdown in the 18-month OS rate grouped by SUV max. The red line showing SUV max less than or equal to 15 with an 18-month OS rate of 38% and the blue line showing SUV max greater than 15 and an 18-month OS rate of 56%.

This looks at the 18-month OS rate estimate based on metastasis site. The blue line, which you can see here on the left is bone mets only with a 51% 18-month OS rate. The red line shows lymph node only mets with a 79% OS rate at 18-months. The green line showing bone and lymph node metastasis with an 18-month OS rate of 79%. And the orange line with any visceral metastasis with an 18-month OS rate of 52%.

This looks at the 18-month OS rates by PSA response after the first cycle of Lu-PSMA and patients that had any PSA decrease in blue on the figure on the left had a 71.2% 18-month OS rate compared to those who had increased after the first cycle in red, OS rate at 18-months of 56%.

This is the same figure but after the second cycle of Lu-PSMA. So a PSA decrease in blue, 81% 18-month OS rate with a much lower 18-month OS rate for those who had a PSA increase at 18 months of 48%.

This looks at the breakdown by PSA responders. In blue, the PSA responders had a 79.3% 18-month OS rate compared to non-responders in red who had a 42.3% OS rate.

And this study looks at the 18-month OS rate by response. Non-responders in red, obviously the worst curve on this figure and relatively similar between blue, which is other, less than 50% decreased responders. Orange was the good responders and green which is the exceptional responders, which you can see here are significantly better on the curve than the non-responders in red.

So this table basically summarizes the previous figures, which we discussed. To quickly summarize, looking at the 18-month OS rates based on PSA change from baseline, any decrease between the first and second cycle, 71.2% versus an increase of 61.8%. Between the second cycle and further treatment, no decrease in PSA, 81% versus 48%. Other treatment courses, so the exceptional responders, which is based on greater than 90% PSA decrease, 80% 18-month OS rate, 82.3% for the good responders, 77.8% for the other responders, and 42.3% for the non-responders.

So, several discussion points from this trial, this single-center experience of Lu-PSMA determined a 12-month overall survival rate of 75% and an 18-month overall survival rate of 64%. This shows that Lu-PSMA is competitive when compared to other treatment options for patients with mCRPC. By way of comparison, looking at the Cougar 301 trial (COU-AA-301), with abiraterone, 15.8 months, and the ALSYMPCA trial for radium-223 of 14.9 months. The study also showed that patients that observed any decrease in PSA following two cycles of Lu-PSMA had significantly improved overall survival and this is a good indicator for further treatment response of overall survival. Ultimately in practice, this may prove to be a potential time point in which patients and clinicians can reassess suitability for the continuation of Lu-PSMA therapy.

In conclusion, this study reported an 18-month overall survival rate of 64% among patients with mCRPC undergoing Lu-PSMA. Serum PSMA responses from baseline after treatment cycle two was an indicator of response and overall survival. Other parameters, which we discussed, including PSA baseline less than 20, SUV max more than 15, and certain metastatic sites, including lymph node only or bone and lymph node metastases were suggestive of improved overall survival. And finally moving forward, this information will be utilized in practice to further improve the evidence basis for Lu-PSMA therapy.

Thank you very much and we hope you enjoyed this UroToday Journal club.
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