Neal Shore, MD, FACS

Let me take this opportunity to go around the horn for some closing and final thoughts. Larry, let’s start with you, and then we can go to Steven and then Michael, please.

First, thanks for including me in this exciting, stimulating discussion. But as a nuclear radiologist, I feel that PSMA [prostate-specific membrane antigen]-targeted imaging, and now we are talking about therapy, is a game changer, and that’s how I refer to it. It’s the most impactful breakthrough in the diagnostic imaging that I have seen in my career. We’re just beginning to realize the benefits on an imaging level, and then as a therapeutic agent. And theragnostics, we could spend another few tumor boards talking about theragnostics, but the implications are tremendous, and it’s just the tip of the iceberg. So thanks again, it’s a great time.

Let me echo that by saying it’s an absolute pleasure to be on this wonderful panel today, moderated by Neal. For me, it’s an incredibly exciting time to be a radiation oncologist who is interested in prostate cancer. When we look at the data that we talked about today from an imaging standpoint, it’s clear that next-generation imaging is going to continue to change the way we practice. As Neal alluded to, the VISION trial is a model system for showing how radiation drugs, radiotherapeutics, theragnostics, these words that we are talking about, drugs that can be given that have a radiation flavor that are tied to next-generation imaging, are going to be very important in the years to come. There are a lot of people watching this who are interested in this, but there are a lot of people I know out there who are not quite sure about where this is all going. All of the fancy imaging that we’re talking about is going to directly impact the way we take care of patients, all of us as urologists and radiation oncologists, and medical oncologists. I would encourage those who are watching today to get yourself educated because there is a lot of exciting work that is going to be coming down the pike.

Thank you Steven, and final thoughts, Mike.

Thank you. I want to echo the other panelists in thanking Dr Shore and 

® for organizing this evening’s tumor board. It has been fantastic participating with the other panelists. I would echo the comments of the earlier speakers about my excitement pertaining to PSMA-targeted imaging. I feel it has clearly made a substantial difference in our ability to risk stratify patients, determine the most appropriate therapies, and so forth, in particular in the initial staging evaluation in the biochemical recurrent space.

Clearly, some questions remain as we move into more advanced disease settings, and that evolves around, are we putting patients in the correct categories with respect to where different therapies have been approved? There are also questions surrounding the appropriateness of using metastasis-directed therapy with PSMA imaging and its role with following response to therapy. That’s really the 2.0 of PSMA-targeted imaging research, to figure out the answers to all those questions. It’s just the tip of the iceberg, especially with PSMA theragnostics now coming down the pipeline. We are going to see even more PSMA-targeted agents in the way of things like CAR [chimeric antigen receptor] T-cell therapy targeting PSMA, and so forth. It’s just the beginning of the story here and there is so much to learn, and it’s an amazing and exciting time to be a urologist.

Gentleman, thank you so much. Dr Steven Finkelstein, Dr Larry Saperstein, and Dr Michael Gorin, you guys are awesome. Thank you for all the preparation you did for this. Thank you for sharing your cases. Thank you for all the clinical trials, research, and education that you have done and continue to do.

To our viewing audience, it was a pleasure to have your attention and be part of 

® today. On behalf of all the faculty, we hope you found this to be valuable, especially the case presentations as well as the review of the data. I hope you can take a lot of this information from a practical standpoint back to the clinic. Like all of us, we are looking forward to additional studies. We have unmet needs and answers that we have to come up with, and that’s the exciting part for all of us being physician scientists.

Once again, gentlemen, thank you so much, and thank you everybody for listening.

Videos

Prostate cancer experts highlight some closing thoughts and exciting research in progress on prostate cancer imaging.

The Future of Prostate Cancer Imaging

I don’t know that we want to go into a lot of discussion on it, but we alluded to this earlier, the importance of PSMA [prostate-specific membrane antigen] PET [positron emission tomography] vis-à-vis the enhancement of diagnostic imaging. Then there is the second component of bringing in the PSMA antibody conjugates with a radiopharmaceutical in the form of a beta particle. This is the VISION trial, utilizing lutetium and PSMA for patients who were PSMA positive, and 87% of the patients at baseline had a positive PSMA scan. This was in a group of patients who were heavily pretreated with prior taxane, 1 or 2 novel hormonal agents [NHAs], and then were randomized to Lu-PSMA-617 vs best standard of care, but a taxane, cabazitaxel, was not part of this. But even with this caveat, this was probably the most important data that came out of the ASCO 2021 [American Society of Clinical Oncology annual meeting] and essentially demonstrated that the primary analysis, the rPFS [radiographic progression-free survival], and I will show in a second the OS [overall survival], hit their end points with a statistically significant hazard ratio. Here on the rPFS, it is 0.4, in a heavily pretreated and high tumor burden population. Here is the OS primary end point, also demonstrating its significance.

What’s interesting and important now is what we talked about, theragnostics. Most of us are expecting this will lead to FDA approval for patients with mCRPC [metastatic castration-resistant prostate cancer] post-chemotherapy, post-NHA. We expect this approval to certainly happen in the very near term, and this will open the flood gates for other important trials looking at both other beta particles and alpha particles in the form of, most classically used globally would be actinium. There are others even combining beta and alpha particles, and even small molecules as well. This is an exciting area that our colleagues need to stay tuned for. Much like PSMA PET, it’s not about if, it’s only when you will be utilizing this novel mechanism of action strategy. Like in VISION and so many other advanced prostate cancer therapeutics, it will start to be interrogated prechemotherapy and even within metastatic castration-sensitive disease.

Neal Shore, MD, FACS, reviews the VISION clinical trial in prostate cancer imaging.

Prostate Cancer Imaging: the VISION Trial

Great discussion. Let’s go to our last case, and it’s interesting because it’s into this area of the nmCRPC [nonmetastatic castration-resistant prostate cancer], or what we used to call index case 1 AUA [American Urological Association] M0. Larry, would you like to review this?

A 62-year-old man presents with reduced urinary flow and hematuria. Past medical history is significant for hypertension controlled with medication. Family history, father had lung cancer in his early 70s. Clinical work-up, PSA [prostate-specific antigen] is 7.9 ng/mL. Prostate biopsy shows Gleason score of 7 (4+3). Treatment and follow-up, the patient undergoes robotic-assisted laparoscopic prostatectomy and pelvic node dissection. Results show pT3b, focal extracapsular extension and seminal vesicle invasion, margins negative, N1, M0. Postoperative PSA is 0.53 ng/mL. The patient undergoes adjuvant radiation therapy and is started on leuprolide. PSA is undetectable. Follow-up, 2 years later the patient presents with rising PSA of 0.5 ng/mL, 4 months later PSA is 0.8 ng/mL.

This is a classic patient with nonmetastatic castration-resistant prostate cancer. The next question, if we are going to a tumor board now compared to just a few years ago when we were doing the phase 3 trials, the SPARTAN, PROSPER, and ARAMIS that led to the approval of those 3 androgen receptor [AR] drugs, respectively apalutamide, enzalutamide, and darolutamide. Those were all done on conventional imaging using CT scan and technetium bone scan, and they had to be negative, had to have a doubling of less than 10 months to get into those trials comparing the AR inhibitor vs placebo. Now, I guess the question is what’s the role for PSMA [prostate-specific membrane antigen] PET [positron emission tomography] in nmCRPC? This is summarizing the points I was making. Perhaps Larry you want to comment on this nice work that was done by [Wolfgang] Fendler, [MD,] and colleagues and looked at the use of PSMA PET in these patients who would have qualified for SPARTAN, PROSPER, or ARAMIS. What are your thoughts about the results of the PSMA PET in these patients?

It’s an interesting retrospective study. Probably to do it justice, I am going to respectively defer to my clinical colleagues.

I’ll go on with it because I know this well. Of 200 patients who would have been in enrolled in SPARTAN, PROSPER, and ARAMIS, 98% had positive findings. About 55% had findings within the pelvis and 45% above the pelvis based upon PSMA PET. But it gets back to our prior conversation, how would that change what you would do? Today, those 3 trials have led to the level 1 evidence in virtually all of our international guidelines, including NCCN [National Comprehensive Cancer Network], that says if the doubling time is less than 10 months, go with an AR inhibitor, apalutamide, enzalutamide, or darolutamide. It’s interesting, the label for those drugs doesn’t talk about the doubling time. But it is still fascinating in this paper that 198 of the 200 patients who would have had no findings, were found to have clear findings, and half had disease findings above the pelvis. What are your thoughts about that? Maybe I will ask Mike first and then Steven.

Because many of these drugs are approved in every line of therapy now, whether it’s newly diagnosed metastatic prostate cancer, nonmetastatic castration-resistant, or metastatic castration-resistant, in some ways it’s neither here nor there because they are going to see all these different lines of therapy anyway. But imagine a scenario where the patient has seen androgen deprivation, they have received an androgen receptor blocker, and they haven’t received docetaxel yet. And docetaxel wouldn't be indicated in nonmetastatic castration-resistant, but we know it would be in metastatic castration-resistant. Here, almost half of the patients have metastatic disease, can we start pulling the trigger and moving docetaxel into an earlier line of therapy for these patients who did not see it in their first or second course of treatment? There are no data to support doing that of course, but it really begs the question of whether these patients could potentially be candidates for that in the future.

I think we are going to find a situation where the imaging gets so good that we are going to be able to find sites of disease in every patient we look at, where the PSA is rising. However, what we are defining is its own unique subset. It’s not that we couldn’t find it anymore, it’s just low volume disease. It’s disease where you need next-generation imaging to be able to find it, and we know those drugs worked when we couldn’t point to where the individual spots were. We know these drugs will work when we say it’s low volume disease, it’s only detectable by fancy next-generation imaging. I don’t want us as specialists to throw the baby out with the bath water. We should embrace the history of what we have done. The imaging is going to drive, “Oh my goodness, there is a whole bunch of disease we see on this picture, or hey, there is only a little bit of disease on this picture.” We are going to be able to temper our enthusiasm for pulling the right treatment at the right time in the right patient.

Now, a lot of this is undiscovered country. We have to do those trials to use the imaging with some of the agents that we have classically used to find out if there are better agents to potentially use in certain scenarios. But like Mike alluded to, a lot of drugs that we use are indicated across the spectrum of the prostate cancer continuum. I think we are going to find that a lot of these drugs are just going to be moved up as we are able to find the disease and point to it sooner.

A look at the patient profile of a 62-year-old man presenting with reduced urinary flow and hematuria.

Patient Profile 7: Gleason 7 Prostate Cancer

A 64-year-old man is found to have a firm bilateral prostate nodule of 1.8 mm on his routine physical exam

Family history of prostate cancer (father, uncle)

Transrectal ultrasound (TRUS)-guided biopsy of the prostate confirms advanced adenocarcinoma of the prostate and Gleason score of 8 (4 + 4)/Grade Group 4

MRI is negative for pelvic LN involvement but positive for one 1.1-cm mediastinal supraclavicular LN (T2bN0M1a)

Germline multigene testing of biopsy specimen revealed a 

Patient was started on leuprolide and abiraterone; scheduled for physical exam, PSA assessment, and imaging every 3 months.

By the second follow-up visit (6 months after initiating treatment; August 2017), PSA levels declined to 2.1 ng/mL and prostate nodule size was 1.4 mm.

Patient’s disease remained stable through August 2018 (18 months of treatment).

21- and 24-month Follow-up Notes (November 2018, February 2019)

Patient’s PSA levels increased to 46.9 ng/mL in 11/2018 and 73.7 ng/mL in 2/2019.

MRI revealed that the size of the existing positive LN increased to 1.3 cm, and revealed a new, faintly positive 0.9-cm para-aortic LN.

Given the recent findings and the patient’s known 

 mutation status, the patient and clinician decide to initiate olaparib 300 mg BID.

The biggest challenge is that patients will die. And unfortunately, even if they get exposed to now all of the novel mechanisms of action, and we are challenged to still understand how to best combine some of these, how to sequence. Ultimately, if the patient has good cardiovascular health and an intact bone compartment so they’re not becoming overly myelosuppressed, they ultimately will succumb to the disease. But we’ve made great progress. The median overall survival for an asymptomatic patient with mCRPC [metastatic castration-resistant prostate cancer], which was 19 months in 2010, is now closer to 3-and-a-half years in 2022. It’s a virtual doubling. We have many patients now who are living 5, 6, 7 years with advanced prostate cancer, especially those even with CRPC. So we’re making great strides, but ultimately, we’re not curing the disease. That’s why clinical trials are a standard of care. I certainly implore all of my colleagues to think about clinical trials whenever possible.

In terms of future directions, besides earlier use of PARP inhibitors, are there any other interesting drugs or combinations in the pipeline addressing the unmet needs? Gosh, there are so many. There’s some great work going on with CDK4/6 inhibition. There’s work going on with ATM, ATR pathways, 

 loss, PI3K, AKT pathways, and a lot of really good work looking at combining other therapies to lessen resistance. That I think is one of the interesting aspects of taking a PARP inhibitor in combination with an AR [androgen receptor] pathway inhibitor, increasing the responsiveness of a PARP inhibitor to a patient who’s HRR [homologous recombination repair] negative, while at the same time adding a PARP inhibitor and decreasing the likelihood of developing AR resistance. Is there a difference among the PARP inhibitors? A lot of this work remains to be investigated, discussed, and described.

Finally, what clinical pearls do I have for community oncologists treating patients with metastatic CRPC? I would say it’s an incredible time to be importantly current with the literature. At ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], we saw 3 incredibly important studies, PROpel, MAGNITUDE, ARASENS. There are additional studies that’ll be forthcoming in virtually every one of our major congresses, which will allow us to have an even more full-throated conversation with patients regarding their options. We recently had the approval of lutetium-617, the first phase 3 trial demonstrating survival benefit utilizing the novel mechanism of action of a PSMA ]prostate-specific membrane antigen] radioligand therapy. That adds yet another, or what I would describe as the seventh, novel mechanism of action for patients with advanced prostate cancer. We now have 12 life-prolonging agents to pick from within the 7 novel mechanisms of action.

The challenge to our community oncologists, whether they’re radiation oncologists, urological oncologists or medical oncologists, is to make sure that if your patient succumbs to advanced prostate cancer, that he doesn’t just have 1 to 2 level 1 evidence-approved therapies, but that indeed he got as many of the 7 novel mechanisms of action as possible. It’s also important that we are able to be really good stewards of the adverse effect, safety profiles that are unique to each of them, and to offer them in a way that’s propitious. Then of course globally, we’re all challenged with trying to get access to these new drugs, which is oftentimes challenging because of accessibility, either physically or economically. As physician-scientists, that’s a high priority for all of us.

Thank you very much. I appreciate your attention.

Neal Shore, MD, FACS, muses about the unmet needs in metastatic prostate cancer treatment and shares clinical pearls for community oncologists.

Neal Shore, MD, FACS

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The Future of Prostate Cancer Imaging

Prostate Cancer Imaging: the VISION Trial

Patient Profile 7: Gleason 7 Prostate Cancer

Current Challenges and Future Directions in Metastatic Prostate Cancer