Prostate Cancer Radiopharmaceuticals: PSMA and Lutetium Updates

•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. 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. 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).

•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.

•If you are metastatic castrate-resistant, you can get radionuclides (a radioactive particle which attaches to the surface of prostate cancer cells, such as the Prostate Specific Membrane Antigen), like lutetium-177 (Pluvicto), or you can get a checkpoint inhibitor (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. For example, if yo 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?

•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. 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. Oliver Sartor discussed the latest advancements in prostate cancer treatment, emphasizing the importance of understanding the disease's stages (castrate-sensitive and castrate-resistant) and the role of novel therapies. He highlighted the use of radioligands like Pluvicto and J-591 lutetium, and the potential of alpha particles for targeted therapy. Dr. Sartor also addressed the challenges of neuroendocrine prostate cancer, suggesting platinum-based therapies and DLL3- targeted treatments. He stressed the importance of bone health management. There is a need for clinical trials to evaluate new combinations. Dr. Sartor concluded by encouraging patients to stay informed and engaged in their treatment decisions. OUTLINE Overview of Prostate Cancer Treatments

•Dr. Oliver Sartor is an expert on new pathways and novel targets in prostate cancer.

•Prostate cancer is divided into castrate-sensitive and castrate-resistant stages, and each has standard therapies.

•He discusses the use of novel hormones like enzalutamide, apalutamide, and abiraterone, and the role of PARP inhibitors and genetic testing in precision medicine.

•Therapies which target a genetic mutation are only useful in about 20% of cases. Circulating Tumor DNA and Oligo Progression

•Circulating tumor DNA (ctDNA) is a biomarker which can be used to monitor disease response and progression.

•For patients with oligo progression (a few metastatic sites), this limited disease progression can be treated with stereotactic body radiotherapy (SBRT).

•A patient who achieved durable remission with J-591 lutetium and SBRT alone. Targeted Therapies and Protein Degraders

•There are a variety of targeted therapies, including AR-targeted, PSMA-targeted, and DNA repair-targeted.

•The AR degrader ProTac has potential for treating castrate-resistant prostate cancer.

•Other degraders are in development, including RV-766 and an interesting degrader from Bristol Myers Squibb. Cell Surface Targets and Theranostics

•Cell surface targets provide a hook that drugs can latch onto, such as PSMA-targeted (Prostate Specific Membrane Antigen) therapies, including antibody drug conjugates (which grab an antigen on the cancer cell one side and deliver a chemotherapy payload on the other) and bispecific antibodies (which grab an antigen on the cancer cell on one side and deliver a T-cell on the other).

•Theranostics is the use of radioactive tags which latch onto cancer cell antigens to diagnose and treat cancer.

•Different isotopes, such as gallium-68, actinium-225, and terbium-149, are being explored in theranostic (radionuclide) applications. Challen Challenges and Future Directions in Prostate Cancer Treatment

•The challenges of treating prostate cancer include the need for better targeting and understanding of tumor biology.

•Alpha particles have a potential role in targeted therapy.

•There are many ongoing clinical trials.

•More attention needs to be paid to combining different therapies to achieve better outcomes. New Treatment Options

•Vic Paglisotti asked about the use of radium-223 and enzalutamide post-Pluvicto, and Dr. Sartor explained the benefits and precautions.

•Nathanael Jackson inquired about the best combination therapies, and Dr. Sartor suggested considering hormonal agents and bone-targeted agents.

•Paul Van Camp asked about identifying neuroendocrine prostate cancer, and Dr. Sartor outlined the use of circulating tumor DNA, LDH, and specific markers. Deepak asked about the use of calcium supplements and PARP inhibitors, and Dr. Sartor provided practical advice and insights. Final Thoughts and Closing Remarks

•Dr. Sartor emphasized the importance of finding a good doctor and staying informed about treatment options.

•Continued research is needed, such as in new therapies like targeted alpha therapy.

•Patients should ask questions and stay engaged in their treatment decisions.