“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals”

“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals” (Oliver Sartor, MD) [#122] Brad Power November 25, 2024 “CRPC is incredibly active. The post-lutetium space is big. There are lots of new, interesting things in development.” – Oliver Sartor, MD “I love radiopharmaceuticals, because I can see it and I can treat it, and that gives me a power that I can't otherwise have.

” - Oliver Sartor, MD “I mentioned cell surface targets, and there are a bunch of ways to bind to that target. This is where we have a lot of innovation. Here we have small molecules, peptides, antibodies, different ways of approaching this.

A lot of what you're going to see over the next five to 10 years is people taking these isotopes, bringing them onto the cell surface with a diversity of targeting molecules. We're not going to be stuck with PSMA-617.

” – Oliver Sartor, MD “Hopefully I was able to provide a little bit of an insight for people here and there, but you've got a well educated group, and keep at it, because that education gives you power, and when you're empowered, you can make better decisions, and that's what it's all about: trying to get to the best decision.

” – Oliver Sartor, MD Meeting Summary Advanced cancer patients often find themselves trying treatments that work for a while until they fail, then moving on to another therapy. There are many treatment options for some cancers, like prostate cancer, and new ones are becoming available continuously.

New drugs which take a radioactive payload and tie it to a cancer cell (a radiopharmaceutical) are now coming to market in new combinations. Different kinds of radioactive particles can be used. These particles can be combined with radiation sensitizers, modulating the way the drugs alter DNA. As a patient or physician, what you thought was the state of the art can change in six months.

You need to keep a constant outlook to know what is newly available and what might be available in the coming year. A. Oliver Sartor, MD, of the Mayo Clinic, is uniquely qualified to review this complicated landscape and discuss research on radiopharmaceuticals, other treatments, and combinations in prostate cancer.

His research has mainly focused on translational science and clinical research trials of advanced prostate cancer since 1990, and he is recognized as an expert in that field through his contributions to the practice and the publishing of over 500 peer-reviewed articles and numerous book chapters and reviews.

He has been principal investigator or co- principal investigator on pivotal trials that have helped to change the landscape of advanced disease including radium-223, cabazitaxel, and Pluvicto (PSMA-617 Lu-177). What are the standard tests for prostate cancer today?

“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals” (Oliver Sartor, MD) [#122] Most men monitor their risk of prostate cancer through a blood test, the “PSA” (prostate specific antigen

xel, and Pluvicto (PSMA-617 Lu-177). What are the standard tests for prostate cancer today?

“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals” (Oliver Sartor, MD) [#122] Most men monitor their risk of prostate cancer through a blood test, the “PSA” (prostate specific antigen) test and a “digital rectal exam” (your doctor puts a finger up your rectum and feels for lumps or other abnormalities).

If your PSA is rising, you can get a “needle biopsy” from the prostate - tissue samples are taken, stained, and examined. You can also get “MRI” (magnetic resonance imaging) and ultrasound for non-invasive images.

To determine if your cancer has spread – to check for “metastases” (progression of the cancer away from the primary site of the prostate), you can get a “PSMA PET” scan (prostate specific membrane antigen, positron emission tomography; a radioactive tracer is injected which lights up where sugar is taken up – which indicates cancer – creating a 3D picture of the inside of your body.

) You can also get other imaging tests like a CT scan, MRI, bone scan, or ultrasound. And a biopsy of your metastatic lesion can provide useful information. What are other tests that you should consider? ●Genetic testing: DNA and RNA sequencing of your tissue biopsy to look for genetic mutations, which can point to drugs targeted at those mutations, e.g., BRCA1 or BRCA2.

Genetic testing identifies actionable treatments targeted at identified mutations for about 20% of patients. ●Liquid biopsies: A blood draw can be analyzed to enable DNA and RNA sequencing to look for mutations and monitor disease response and progression.

ctDNA (circulating tumor DNA) can provide useful information, and because it is not invasive, can be taken periodically to monitor your disease. Circulating tumor DNA is not necessarily helpful for identifying sensitive mutations, but you can follow your disease and see what's responding and what's not responding.

●Functional testing : If you have fresh tumor tissue, you can apply drugs (chemotherapy or targeted drugs) to test their efficacy and predict whether you will likely respond. ●Blood test for testosterone : Monitoring your testosterone levels can be important to measure, especially if you are cycling on and off hormone deprivation therapy.

●Spatial or single cell analysis : This advanced test looks at the tumor microenvironment and can help determine if you will be a likely responder to an immunotherapy. ●Microsatellite instability : Microsatellite instability (MSI) is an analysis of your “microsatellites” (short, repeated DNA sequences) in your normal and tumor cells.

If your cancer cells have a high number of mutations in microsatellites, you have a better prognosis and response to immunotherapy. ●Mismatch repair deficiency : You can have your tumor tissue stained to look for mutations in genes that are responsible for correcting DNA errors.

If your cancer cells have a high number of mutations in microsatellites, you have a better prognosis and response to immunotherapy. ●Mismatch repair deficiency : You can have your tumor tissue stained to look for mutations in genes that are responsible for correcting DNA errors. When mismatch repair is deficient, DNA errors go unrepaired, which can lead to cancer.

If you have mismatch repair deficiency, you are a candidate for immunotherapy, specifically using immune checkpoint inhibitors (a type of cancer immunotherapy drug that helps the immune system identify and attack cancer cells), like pembrolizumab (Keytruda). ●FDG PET: An alternative to the standard PET scan (which measures sugar uptake), which can identify neuroendocrine cancer.

“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals” (Oliver Sartor, MD) [#122] What are the standard treatments for prostate cancer today?

Prostate cancer is typically categorized along two dimensions: “castrate sensitive” (responsive to hormone deprivation therapy) or “castrate resistant” (your cancer continues to grow even when your testosterone levels are low, as if you were castrated), and “metastatic” (the cancer has spread beyond the prostate) or “local” (limited to the prostate).

●If you have “localized” disease (only at your prostate), you can get local therapy (surgery or radiation) with or without androgen deprivation therapy (drugs which lower your testosterone) and with or without abiraterone (or other drugs which block your androgen receptor) or no therapy (watchful waiting).

●If you have progression to one to four additional sites (“oligo-progression”), they can be treated with radiation (stereotactic body radiotherapy). ●If you then have rising PSA (prostate specific antigen, a blood test which measures your prostate cancer), you can then get “salvage” radiation, with or without androgen deprivation therapy, or androgen deprivation therapy, or no therapy.

●If you have metastatic prostate cancer which is responding to androgen deprivation therapy, you can get a combination of androgen deprivation therapy plus chemotherapy (docetaxel) or androgen blocking therapies (abiraterone, apalutamide, or enzalutamide), or all three together (a “triplet”).

●If you have non-metastatic (your cancer has not spread from the original site in your prostate) castrate-resistant (your cancer continues to grow even when your testosterone levels are low, as if you were castrated) prostate cancer, you can get androgen receptor drugs (enzalutamide, darolutamide, apalutamide).

●If you have metastatic castrate-resistant prostate cancer, and you haven’t had chemotherapy, you can get immunotherapy ( sipuleucel-T, also known as Provenge) or androgen receptor blocker drugs (abiraterone, enzalutamide). ●If you have metastatic castrate-resistant prostate cancer, you can get chemotherapy (docetaxel).

high number of mutations in microsatellites, you have a better prognosis and response to immunotherapy. ●Mismatch repair deficiency : You can have your tumor tissue stained to look for mutations in genes that are responsible for correcting DNA errors. When mismatch repair is deficient, DNA errors go unrepaired, which can lead to cancer.

If you have mismatch repair deficiency, you are a candidate for immunotherapy, specifically using immune checkpoint inhibitors (a type of cancer immunotherapy drug that helps the immune system identify and attack cancer cells), like pembrolizumab (Keytruda). ●FDG PET: An alternative to the standard PET scan (which measures sugar uptake), which can identify neuroendocrine cancer.

“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals” (Oliver Sartor, MD) [#122] What are the standard treatments for prostate cancer today?

Prostate cancer is typically categorized along two dimensions: “castrate sensitive” (responsive to hormone deprivation therapy) or “castrate resistant” (your cancer continues to grow even when your testosterone levels are low, as if you were castrated), and “metastatic” (the cancer has spread beyond the prostate) or “local” (limited to the prostate).

●If you have “localized” disease (only at your prostate), you can get local therapy (surgery or radiation) with or without androgen deprivation therapy (drugs which lower your testosterone) and with or without abiraterone (or other drugs which block your androgen receptor) or no therapy (watchful waiting).

●If you have progression to one to four additional sites (“oligo-progression”), they can be treated with radiation (stereotactic body radiotherapy). ●If you then have rising PSA (prostate specific antigen, a blood test which measures your prostate cancer), you can then get “salvage” radiation, with or without androgen deprivation therapy, or androgen deprivation therapy, or no therapy.

●If you have metastatic prostate cancer which is responding to androgen deprivation therapy, you can get a combination of androgen deprivation therapy plus chemotherapy (docetaxel) or androgen blocking therapies (abiraterone, apalutamide, or enzalutamide), or all three together (a “triplet”).

●If you have non-metastatic (your cancer has not spread from the original site in your prostate) castrate-resistant (your cancer continues to grow even when your testosterone levels are low, as if you were castrated) prostate cancer, you can get androgen receptor drugs (enzalutamide, darolutamide, apalutamide).

●If you have metastatic castrate-resistant prostate cancer, and you haven’t had chemotherapy, you can get immunotherapy ( sipuleucel-T, also known as Provenge) or androgen receptor blocker drugs (abiraterone, enzalutamide). ●If you have metastatic castrate-resistant prostate cancer, you can get chemotherapy (docetaxel).

also known as Provenge) or androgen receptor blocker drugs (abiraterone, enzalutamide). ●If you have metastatic castrate-resistant prostate cancer, you can get chemotherapy (docetaxel). ●If you have metastatic castrate-resistant prostate cancer, and you have had chemotherapy, you can get chemotherapy (cabazitaxel) or androgen receptor blocker (abiraterone, enzalutamide).

●If you have metastatic castrate-resistant prostate cancer, and you have BRCA1 or BRCA2 mutations (BRCA1 and BRCA2 are genes that produce proteins that help repair DNA), you can get “PARP inhibitors”, like olaparib and talazoparib, drugs that treat cancer by blocking the activity of PARP – poly ADP-ribose polymerase – an enzyme that helps repair damaged DNA.

PARP inhibitors trap PARP at DNA damage sites, preventing the repair of single-strand breaks, which leads to double-strand breaks that cannot be repaired in cancer cells that are deficient in homologous recombination, causing the cancer cells to die.

“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals” (Oliver Sartor, MD) [#122] (drugs that block proteins that stop the immune system from attacking cancer cells) immunotherapy, like pembrolizumab (Keytruda). About a third of the patients who get Pluvicto have really beautiful responses, about a third do not respond very well, and about a third are in the middle.

How is the standard approach to treating prostate cancer changing? All the novel hormone treatments (enzalutamide, darolutamide, apalutamide, or abiraterone) are being applied as earlier lines of therapy. What are the new therapies being researched in prostate cancer?

●Targeted therapies : There are many cancer cell surface targets in prostate cancer that are being researched: the androgen receptor, PSMA, DNA repair, AKT, B7H3, WNT, DLL3, STEAP1, STEAP2, … And there are many ways to bind to cell surface targets on the prostate cancer cells. This is where we have a lot of innovation.

The approaches include: (a) block cancer receptors and enzymes; (b) degrade proteins; attach different payloads to molecules that grab onto the surface of the cancer cells: (c) antibody drug conjugates - a chemotherapy, (d) radiopharmaceuticals - a radioactive particle, (e) bispecifics - an immune cell; and immunotherapies, e.g., (f) CAR-T and (g) immunologic stimulators and inhibitors.

Over the next five to ten years people will be taking isotopes and other payloads, such as alpha particles, and bringing them onto the cancer cell surface with a diversity of targeting molecules. ●Combinations: There will be combinations of isotopes, alphas with betas, combinations with immunotherapy, and radiation sensitizers.

ng isotopes and other payloads, such as alpha particles, and bringing them onto the cancer cell surface with a diversity of targeting molecules. ●Combinations: There will be combinations of isotopes, alphas with betas, combinations with immunotherapy, and radiation sensitizers.

For example, if you're going to damage your tumor DNA with radiopharmaceuticals, you have the potential to be able to inhibit DNA repair by combining it with drugs which do that, like PARP inhibitors. How should you make tradeoff decisions among these new options and the standard treatments? ●Find a doctor who specializes in your specific situation and who will have the relationship you want, e.g.

, consultative ●Get a second opinion ●Don't be afraid of a clinical trial if you don't have good options that are available as part of the standard of care ●Personalize to your situation: your very specific scenario demands a very specific set of options ●Stay informed about your testing and treatment options; for example, you have to be aware of what's available and what's not ●Ask questions of your medical team and stay engaged in your testing and treatment decisions How can you learn more?

“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals” (Oliver Sartor, MD) [#122] ●See the meeting summary, transcript, and video from our discussion with Dr. Sartor in July 2023 “The Current and Future Landscape of Prostate Cancer Treatment”. ●Research the use of non-standard tests, e.g.

, circulating tumor DNA as a biomarker for monitoring your disease progression, and discuss the new testing and therapy options with your medical team The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

“Update on Prostate Cancer Treatments, Especially Radiopharmaceuticals” (Oliver Sartor, MD) [#122] Meeting Notes KEYWORDS prostate cancer, new pathways, novel targets, castrate sensitive, castrate resistant, precision medicine, circulating tumor DNA, oligo progression, stereotactic body radiotherapy, AR targeted drugs, PSMA targeted drugs, DNA repair targeted drugs, cell surface targets, alpha particles, antibody drug conjugates SPEAKERS Oliver Sartor (73%), Brad Power (15%), Nathanael Jackson (8%), Vic Paglisotti (1%), Paul Van Camp (1%), David Plunkett (1%), Arthur Bruno (0%) CHAT CONTRIBUTORS Allen Morris, Vic Paglisotti, Nathanael Jackson, Alane Watkins, Arthur Bruno, Eric Hall, Noel Resch, Alexander Lalov, Deepak, Rick Davis, James Ward SUMMARY Dr.