Heather Cheng: All right. Well, it's a pleasure to welcome everyone back from lunch for our sixth session, which will be the management of metastatic castration-resistant prostate cancer. We're going to start off with Dr. Matthew Smith from the Massachusetts General talking about Lutetium PSMA therapy.

Matthew Smith: My sincere thanks to Silke [inaudible] for asking me to present on this really important topic. I also want to thank Shahneen Sandhu and Oliver Sartor for sharing slides with me.

So my topics today. I've been asked to cover monotherapy, combinations in patient selection. That's a lot for 10 minutes, but I'll do my best.

So PSMA is a transmembrane carboxypeptidase. It's highly expressed in prostate cancer as you know, and has relatively low expression in most normal tissues. It's been developed as a target for PET imaging, radioligand therapy and adoptive cellular therapy. Based on the results of the VISION trial, I think we can now consider it a validated target in mCRPC.

The Phase 3 VISION study included 831 patients with metastatic castration-resistant prostate cancer and progression after previous treatment with one or two taxane regimens and at least one prior androgen receptor pathway inhibitor. The PSMA PET imaging requirement was that patients required 68 gallium PSMA-11 uptake greater than the liver parenchyma in one or two more metastatic lesions and no PSMA-negative sites of metastatic disease, and we'll come back to that a little later in the talk.

Eligible patients were randomized in a 2:1 fashion to either best standard of care or best standard of care plus lutetium PSMA-617 every six weeks for up to six cycles. Standard of care included receipt of another AR pathway inhibitor, but excluded most other therapies, including chemotherapy.

The primary study endpoints were progression-free survival and overall survival. This was a spectacularly positive trial. Lutetium PSMA-617 markedly improved progression-free survival with a hazard ratio of 0.40 and a highly statistically significant P value. The median PFS in the control group was 3.4 months compared an improvement to 8.7 months with PSMA-617. PSMA-617 also improved overall survival with a hazard ratio of 0.62. Median overall survivals were 11.3 months and 15.3 months in the control group and PSMA-617 groups respectively

In subgroup analyses, the effect of PSMA-617 on overall survival were generally consistent across all of the pre-specified subgroups. I've called out the androgen receptor pathway inhibitors part of planned standard of care to make a specific point, and that is that there did appear to be somewhat greater improvement in overall survival in the group that received an AR pathway inhibitor as part of planned standard of care with a hazard ratio of 0.54 compared to 0.68 in the group who did not receive an AR pathway inhibitor as standard of care. This apparent difference has several potential explanations. It could just be a chance observation in a large controlled trial, could be the result of an unintended bias, or it is also plausible that it resulted from an increased target expression resulting from AR pathway inhibitor treatment. That latter hypothesis is being studied in the context of ongoing trials of PSMA-617 in combination with AR pathway inhibitors.

We've learned a lot else about the effectiveness of PSMA-617 from the very important TheraP trial. TheraP enrolled 200 patients with mCRPC and prior docetaxel chemotherapy. The PET selection was different than in the VISION trial. So TheraP required a PSMA SUV max of greater than or equal to 20 at a site of metastatic disease and SUV max of greater than 10 at all sites of measurable disease, and then patients with discordant FDG and PSMA disease were excluded.

Eligible patients were randomized to PSMA-617 or cabazitaxel with the primary study endpoint of response. Compared to cabazitaxel, PSA-50 response rates were substantially higher with PSMA-617. PSA-50 response with 37% in the cabazitaxel group compared to 66% with PSMA-617. Notably, this greater response rate was seen regardless of baseline PSMA intensity. This is very nice work from the TheraP investigators presented at the most recent ASCO GU. They looked at baseline PSMA intensity as a potential biomarker of response in the TheraP trial. They dichotomized high versus low PSMA intensity using an SUV mean of greater than 10 or less than 10.

In both groups, PSMA-617 resulted in higher PSA-50 responses than in the cabazitaxel group, although there was a marked difference between high and low baseline PSMA intensity. In the low group, the odds ratio of response in favor of PSMA-617 was 2.2 compared to 12.2 odds ratio in the high baseline PSMA intensity. This marked difference in odds ratio suggests that baseline PSMA intensity may serve as a useful predictive biomarker for response to PSMA radioligand therapy. I hope that'll be a point of active conversation on the panel.

Now, following really establishment of PSMA radioligand therapy as a standard of care from the VISION trial, there's going to be a wave of ongoing planned and future trials that will have us awash in new data using PSMA radioligand therapy. My thanks to Shahneen Sandhu for sharing this slide with me. Here she's nicely summarized a rather extraordinary array of clinical trials looking at PSMA radioligand therapy. Ongoing and planned trials will look at PSMA radioligand therapy using different PSMA targeting compounds and different therapeutic radio isotopes, including actinium and thorium.

Other trials will look at the role of PSMA radioligand therapy in earlier disease states in prostate cancer. Then lastly, ongoing and planned trials will look at combinations of PSMA radioligand therapy with a variety of other classes of drugs, including enzalutamide, PARP inhibitors, and checkpoint inhibitors. I'd say compared to lots of other combination studies in our field in prostate cancer, I think many of these study designs are quite rational, although I won't have the time to go into all the nonclinical evidence supporting that statement.

So I think there's a number of gray areas that emerge from the VISION trial. Even the best trials leave many unanswered questions that I'd argue that in some ways it's the positive, good practice changing trials that maybe lead to the most provocative questions. But I outlined just a couple of, I think, very pragmatic questions that arise from the VISION trial and particularly as it relates to the FDA approval in the United States.

So are PET tracers, other than 68 gallium PSMA-11 sufficient for patient selection? That is a specific part of the FDA label in the United States. What is the role of PSMA-617 for patients who are unfit for docetaxel? Lastly, is there a role for retreatment of patients who respond to PSMA-617 or other PSMA radioligand therapies?

In summary, in patients with heavily pretreated, mCRPC PSMA-617 significantly improved progression-free and overall survival. It is a new standard of care in heavily pretreated patients with mCRPC. Baseline PSMA intensity appears to be a predictive biomarker for response to PSMA radioligand therapy. Ongoing and future studies will evaluate a variety of important questions and settings, including the efficacy and safety of PSMA radioligand therapy with different targeting compounds and with different therapeutic radioisotopes. Those studies will evaluate the role of PSMA radioligand therapy in earlier prostate cancer disease state. Then lastly, they'll evaluate the efficacy and safety of rational combinations of PSMA radioligand therapy with other drugs, including AR pathway inhibitors, PARP inhibitors and checkpoint inhibitors. Thank you.