Christopher Wallis: Hello, and thank you for joining us for UroToday Journal Club discussion. Today, we're talking about a recent publication entitled the Comparative Effectiveness of Immune Checkpoint Inhibitors versus Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer. 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.

This is the citation for this recent publication led by Dr. Agarwal and his team. Immunotherapy in metastatic castration-resistant prostate cancer is a bit of a hot topic, but, unfortunately, has been less fruitful than many of us have hoped. We know that immunotherapy is effective in many cancers and has become standard of care in urology or urological oncology, at least for patients with metastatic kidney cancer, as well as in advanced bladder cancer.

However, in metastatic castrate-resistant prostate cancer, response rates have been generally poor, and further, PD-L1 metastasis has not shown an ability to predict responses to immunotherapy. And as a result, there's been considerable interest in identifying alternative biomarkers that may provide more clinically actionable information.

The only currently approved immunotherapy approach using immune checkpoint inhibitors in patients with advanced prostate cancer is that of pembrolizumab, which was approved in a tumor agnostic way for all patients with micro-satellite instability or tumor rotational burden greater than 10 per mega-base. However, the trials that supported this indication included relatively few patients with prostate cancer, so better understanding the predictive value of these markers in our patients is of utmost importance.

So, if we look here at some data across tumor types, we can see that prostate cancer is not particularly enriched for mutational burdens. However, we see in a small single-center study that when patients do have high micro-satellite instability, PSA50 responses are quite good with immunotherapy. And if subset analysis of the CheckMate 650 study suggested similarly favorable responses among those patients with MSI high status.

However, we need to consider this always in the context of alternative treatment options. And anytime we're offering a patient with advanced prostate cancer immunotherapy, we need to consider what else we may be able to offer them. And in most cases, these patients have seen androgen access as signaling agents, and chemotherapy is the relevant comparator.

And so, these authors examine the Flatiron Health/Foundation Medicine identified clinical genomic database to help address this issue. This data set includes 280 US cancer clinics and provides a retrospective, a longitudinal database that is linked with clinical data to genomic data using a deterministic matching algorithm. The authors included men with mCRPC diagnosed between January 2011 and April 2021 who underwent comprehensive genomic profiling.

Tumor rotational burden was assessed using a tissue biopsy, and patients were included based on treatments with single-agent anti-PD-1, single-agent taxane. And for the most part, these were used as later line therapies after failure of prior treatment. Genomic profiling was performed with both tumor mutational burden quantified as well as a micro-satellite instability determined. The authors performed a pre-specified comparison of the efficacy of immune checkpoint inhibitors compared to taxane-based chemotherapy, stratified by tumor mutational burden status and they dichotomized this around end mutation for mega-base.

And they assess three outcomes, PSA response, time to next therapy, and overall survival. PSA response was assessed where there was an available baseline PSA within 60 days of starting the therapy and a separate value, at least one to 180 days after starting therapy. Where multiple values were available, they used the one prior to treatment that was most proximal to treatment initiation and then at 12 weeks after treatment.

The time to next therapy was calculated from the start of the treatment to the start of the next treatment or to the last clinic visit if a next treatment had not yet commenced. The authors performed right censoring for death, and among those who did not started another line of therapy. Now I'm going to hand over to Zach to walk us through the results of this analysis.

Zachary Klaassen: Thanks, Chris. This is the patient recruitment flow chart for the study. As you can see, there was more than 7,000 patients initially evaluated. Ultimately, there was line of therapy from 741 unique patients in the mCRPC setting of single-agent immune checkpoint inhibitor or taxane therapy with tissue biopsy. And after excluding 134 patients that did not have PSA response available, there were 607 patients, including 33 that underwent immune checkpoint inhibitor therapy and 574 that had taxane therapy.

So, this is the patient characteristics by line of treatment among patients with mCRPC. As you can see here, there was no difference between ages four. This study in terms of patients with immune checkpoint inhibitor age of 72, taxane, age of 70. Mutational burden was higher for immune checkpoint inhibitor patients at 3.5 versus 2.5 in the taxane group, and PSA, although not statistically different, was higher for taxane therapy patients at 80 versus 63.9.

In terms of treatment line, looking at the immune checkpoint inhibitors, 57.8% of patients had fourth line or greater. 38.8% in the taxane group were more than fourth-line therapy. Majority of these patients, based on the dataset, were in the community practice. Looking at the treatment received, immune checkpoint inhibitors, two patients receiving atezolizumab, nine patients receiving nivolumab, 34 patients receiving pembrolizumab, and about a 50:50 split in a taxane group between cabazitaxel and docetaxel.

This is the waterfall pot looking at PSA response by single-agent Anti-PD-1 access therapy. The dark blue is tumor mutational burden less than 10 mutations per mega-base. And the light blue is greater than 10 mutations per mega-base. And as you can see here, the best responses were the light blue patients with greater mutational burden in this sample size of the immune checkpoint inhibitor patients with four patients out of nine, having a greater than 50% PSA decline, and no patients with low tumor mutational burden, achieving that PSA50 response.

As we can see here, a similar waterfall plot for agents for taxane therapy patients, and no real difference between those with low versus high mutational burden for taxane chemotherapy. These Kaplan–Meier curves look at time to next treatment by therapy class, and you can see here that this is for on the left for tumor mutational burden, less than 10. Anti-PD-1 is in orange, and taxane chemotherapy is in this dark blue color. And we can see here that taxane chemotherapy has a significant time to next treatment with a hazard ratio of 2.65 95% confidence interval 1.78 to 3.95.

On the right is the patients with tumor mutation burden greater than 10, and we can see an advantage here for immune checkpoint inhibitor therapy with the greater time to next treatment on the Kaplan–Meier curve. Hazard ratio for this is 0.37 95% confidence interval 0.15 to 0.87. This looks at overall survival by therapy class. Again, stratified by tumor mutational burden. Less than 10, we see no difference between Anti-PD-1 therapy and taxane chemotherapy with a hazard ratio of 1.08, but in the tumor mutational burden greater than 10, we see a survival advantage for the Anti-PD-1 access inhibitors with a hazard ratio of 0.23 and a 95% confidence interval 0.10 to 0.57.

This looks at time to next treatment of patients receiving immune checkpoint inhibitors or taxanes by tumor mutational burden, and this is stratified, as you can see here. A high tumor mutational burden is light blue, low tumor mutation burden is dark blue, and we can see that the patient's receiving immune checkpoint inhibitors that had a high mutational burden had improved time to next treatment with an adjusted hazard ratio of 0.18. When we look at the similar breakdown by taxanes, there's no difference based on tumor mutational burden with an adjusted hazard ratio, not statistically significant of 0.94.

This is the overall survival. You can see that these curves look very similar to the previous slide. Looking at time to next treatment for overall survival, again, for immune checkpoint inhibitor therapy treated patients tumor mutational burden greater than 10, adjusted hazard ratio of 0.25 statistically significant. And again, no significant difference for taxanes based on tumor mutational burden for overall survival.

So, this summarizes what we've just discussed. This is time to next treatment and survival by therapy class based on tumor mutational burden and MSI status. On the left, we see time to next treatment. Looking at the tumor mutational burden and MSI, we see a favor for immune checkpoint inhibitors. So the left of the graph for those patients that had a tumor mutational burden greater than 10 and for those with MSI high status. For micro-satellite stable patients, and for tumor mutational burden less than 10, time to next treatment favors the taxanes.

Moving to overall survival, we see several of these lines crossed in the hazard ratio of one, but we do see tumor mutational burden greater than 10 favoring immune checkpoint inhibitor therapy for overall survival. So, several discussion points from this study, this comparative effectiveness study evaluating a cohort of patients treated with immune checkpoint inhibitors or taxanes was found improved time to next treatment and overall survival in patients with high tumor mutational burden treated with immune checkpoint inhibitors versus taxanes.

In practice, we know that the decision to use immune checkpoint inhibitors versus taxanes will also include other considerations such as patient frailty, cost, and tolerability. Rigorous genomic-centered comparative effectiveness studies are likely to become increasingly important in the coming years. FDA approvals have resulted in PARP inhibitors and immune checkpoint inhibitors being added alongside the existing standard of care therapies of NHT and taxane chemotherapy. And importantly, it will not be possible for control groups of future registration trials to rigorously assess all alternatives in a diversified landscape.

Several limitations from this trial. First, this is not a randomized clinical trial as treatment assignments were at the discretion of the clinician. Secondly, as we saw in the results, the number of patients with mCRPC receiving immune checkpoint inhibitors was relatively small. Third, patients were not restricted by timing of biopsy in terms of archival versus contemporaneous as we know that higher tumor mutational burden is more common in contemporaneous biopsies. And finally, 40.9% of the cohort specimens were from the prostate, thus it is possible there were false negatives with respect to tumor mutational burden threshold assessments.

So in conclusion, the findings of this comparative effectiveness study add validity to the existing FDA approved tumor mutational burden cutoff of 10 mutations per mega-base. These results suggest that immune checkpoint inhibitors may be a viable alternative to taxane chemotherapy in later lines of therapy for patients with mCRPC with high tumor mutational burden.

Thank you very much for your attention. And we hope you enjoyed this URO Today Journal Club Discussion.