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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 systematic review and meta-analysis examining the effectiveness and toxicities of lutetium-177-labeled prostate-specific membrane antigen-targeted radioligand therapy in metastatic castration-resistant prostate cancer. 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. Here is the citation for this recently published impressive paper at European Urology.

Advanced prostate cancer is a common cause of cancer death among older men, and prior to death, nearly all patients will develop castration-resistant disease. If we look over the last 15 years or so, there have been a large number of FDA approvals of novel agents in the metastatic castrate-resistant prostate cancer space, beginning with docetaxel in 2004, based on the TAX 327 data, and since that time, a number of androgen receptor-targeting agents, as well as other chemotherapeutic regimens.

Radiotracers have been developed more recently. PSMA is a target of particular interest, and this is a transmembrane zinc metalloprotease. It ends up being heavily overexpressed in prostate cancer and has therefore been targeted for both diagnostic imaging, as well as for therapeutic purposes. 177lutetium-PSMA is used as a radionuclide, and this is a beta-emitter with limited tissue penetration, thus sparing adjacent normal tissues, and additionally, it has low-level gamma emissions, which allow for simultaneous imaging. 177lutetium-PSMA can be used as a theranostic, and there are two main radiotracers that are used; 177lutetium-PSMA-617 and 177lutetium-PSMA-I&T for investigation and treatment.

The objective of the present study that we are discussing today is to perform a comprehensive systematic review and meta-analysis, including the assessment of the effectiveness of lutetium-PSMA, theranostic therapy, the toxicity and severity of toxicity associated with this, as well as to perform a meta-regression, to assess covariate contributions to observed heterogeneity and results between studies.

In order to do this, the authors undertook a systematic review, and their search strategy comprised a number of variations on 177lutetium-PSMA, including keyword and free-text searches, as well as variations on the term theranostics, and then PSMA. The search was performed using PubMed as of February 18th, 2019, and was restricted to the English language. They included retrospective and prospective studies, which were performed in humans, whether these were single or double arms, and whether they were randomized or observational.

The author's considered their primary outcome to be treatment response, which they defined as a PSA decrease of at least 50% from baseline. If further examined, the proportion of patients with any PSA decrease, the proportion who had a PSA increase in toxicity stratified as any grade or serious, which they defined as grades 3 or 4. An analysis was performed with a meta-analysis of proportions for each of the outcomes. They used a logic transformation with inverse variance, weighting, and random-effects models to allow for assessment with the understanding that there is clinical evidence of heterogeneity. They further performed an analysis of both lutetium-PSMA-617 and litetium-I&T individually, and then an aggregate, and assessed for publication biases in funnel plots.

At this point in time, I will hand it over to Dr. Klaassen to take us through the results of this systematic review.

Zachary Klaassen: Thanks, Chris. This figure here shows the flow chart of the systematic review. There were 250 articles that were identified through database searching and subsequently screened. Ultimately, 138 articles underwent full-text assessment for eligibility, and subsequently, 24 were included in the quantitative synthesis. This is a list of the summary studies included in the meta-analysis here, all 24 studies. There are several points to highlight here. You can see that all of these studies were performed between 2015 and 2019, the majority of these studies were performed in either Germany or Australia, and the majority of which were retrospective. There were only five prospective studies included here. Looking at the sample size, relatively small sample sizes for these studies, with only five studies with 100 or more patients included in the trial.

Looking at the results, this is a series of forest plots that we will show you. The first one looks at the proportion of patients with a greater than 50% decrease in PSA after lutetium-PSMA-I&T or lutetium-PSMA-617. Looking at the bottom, you can see that the proportion is 41% that had a PSA response of greater than 50% after either of these treatments. This is a subsequent forest plot looking at the decrease of 50% or more after more than one cycle of either agent, and you can see that this slightly improves with more than one cycle, 41% on the previous slide, and up to 46% after more than one cycle of either lutetium-I&T or lutetium-617.

This forest plot looks at the proportion of patients with a greater than 50% decrease, just looking at the 617 studies, which was the majority of the studies. You can see here that 44% of patients had a PSA decrease of greater than 50%. Similarly, this is limiting to studies of just I&T lutetium-PSMA, and the proportion is smaller with these patients, at a 36% response rate. And so, ultimately, there are more studies with lutetium-617, and this seems to be driving the effect of a PSA decrease greater than 50%.

This forest plot looks at any decrease after lutetium-I&T or 617. You can see here that 71% of patients had at least some decrease in their PSA value, several studies driving this, you can see here that the Brauer study, 91%, the Hofman study, 97%. This forest plot looks at a proportion of decreased, specific to lutetium-PSMA-617, 70% driving the effect of any PSA to decrease that we saw in the previous slide. This is an interesting forest plot, looking at the proportion of patients showing an increase in PSA after either lutetium-I&T or 617, and there was 27% of patients that actually had an increase in PSA. So very little benefit, at least from PSA as an outcome, with lutetium treatment.

This is a bubble plot showing the proportion of patients with greater than 50% PSA decline after therapy. This plot looks specifically at a time interval between PSA radioligand therapy and PSA measurement. On the left is less than 8 weeks between treatment and PSA measurement and on the right is greater than 8 weeks. And you can see here that, not surprisingly, with a longer interval between treatment and PSA measurement, there is a greater proportion of PSA reduction of more than 50%. This is a similar bubble plot looking at patients with greater than 50% PSA decline after therapy stratified by cycles of radioligand therapy. And as mentioned in the previous forest plots, this is much more impressive, not quite as impressive as the timing of PSA measurement, but certainly, patients with more than one cycle of therapy had a greater than 50% PSA decrease.

This table essentially summarizes the previous slides, looking at serum PSA alterations after PSMA radioligand therapy. On the left, you can see that, specific to 177lutetium-PSMA-617 for patients having a greater than 50% PSA decrease, the estimated proportion was 47%, any PSA decreases at 70%, and any PSA increase was 28%. In the middle of the figure, looking at specifically lutetium-I&T, greater than 50% decrease in 36% of patients, with either I&T or PSMA-517, 41%, greater than 50% decrease, 44%, greater than 50% decrease, only with studies assessing greater than 8 weeks between PSA measurement and PSMA radioligand therapy, and any PSA decrease of 71%. As I mentioned, PSA increase when combining all of these studies was in 27% of patients.

The table looks at the meta-analysis of toxicity after PSMA radioligand therapy. We will focus on the grade 3 and 4 toxicity in the middle of the screen here, and you can see there are several toxicities listed. Most commonly was anemia, at 8%, diarrhea, 1%, elevated ALT, 2%, elevated AST, 1%, fatigue, 1%, leukopenia, 4%, nausea, 1%, nephropathy, 1%, thrombocytopenia, 4%, and xerostomia, 2%. So overall, very well-tolerated in terms of treatment and related grade 3 and 4 toxicity.

Several discussion points from this meta-analysis and systematic review looking at lutetium-PSMA at therapy. The aggregate data from this report showed that 46% of patients with CRPC treated with more than one cycle of PSMA radioligand therapy had PSA reductions of greater than 50%. The pooled estimate proportion of patients with grade 3 and 4 adverse events for all toxicities was less than 10%, as we showed in the previous slide. This may be a result of effective targeting of the cells that express PSMA, thus leaving the normal tissues unharmed.

A limitation of this study was the heterogeneity among the studies. Possible contributors to heterogeneity, which they showed in the bubbles plots, included differences in the number of cycles and the time interval between PSMA radioligand therapy and measuring PSA after therapy.

According to clinicaltrials.gov, there are 15 ongoing trials assessing the role of 177lutetium-labeled PSMA-targeted agents in CRPC. Two that are double-arm studies, that we will highlight here, include the VISION trial, which is a phase 3 trial of 177lutetium-PSMA-617 versus standard of care. And just recently on March 23rd, there was a press release noting that this study met both of its primary endpoints, favoring the lutetium arm, significantly improving overall survival and radiographic progression-free survival. And so hopefully we will see either at, probably, big ASCO in a couple of months or at ESMO, the reporting of these results. Also recently published in The Lancet Oncology in February was the TheraP trial, which was a phase 2 trial of 177lutetium-PSMA-617 versus cabazitaxel, with a sample size of 200 patients, and the PSA response, which was the primary outcome, favored lutetium, at 66% compared to 37% for cabazitaxel.

In conclusion, the relatively high number of PSA responders alongside the low rate of severe toxicity indicates the potential promising role of PSMA radioligand therapy in treating men with CRPC. Data from the systematic review and meta-analysis can serve as a summary of effectiveness and adverse events for treating clinicians in order to balance the risk and benefit of this novel therapy for their CRPC patients.

Thank you very much. We hope you enjoyed this UroToday Journal Club discussing lutetium-177 PSMA therapy.