Personalized Treatment for Advanced Prostate Cancer

•Increase in treatment intensity : Treatment intensification is now standard of care for prostate cancer, involving therapy combinations of a systemic therapy, potent androgen receptor blockers, and perhaps radiating the primary site so that eventually we might be able to stop hormonal therapies. As Bob Gatenby has shared, hitting the cancer hard and early can be more effective due to the reduced heterogeneity of your cancer population at an early stage. In addition to combinations, potent androgen receptor inhibitors are moving into earlier and earlier settings, and earlier use will have implications for subsequent therapies.

•Increase in treatment combinations: For example, combining systemic therapy and radiation can improve prostate cancer outcomes. Another example: “PARP inhibitors,” which regulate DNA repair, are being used in combination with androgen receptor inhibitors.

•Better cancer treatment outcomes for black men : Black men have better outcomes with immunotherapy and with other drugs than white men. In a study with a double androgen receptor drug combination, black men had better outcomes with delayed progression, and better survival. The chance of making it to two years was 86% for black men and 67% for white men.

•Whole health emphasis : Men with prostate cancer are living a lot longer. Patients are enjoying remissions, but they're also suffering from the side effects of the treatments. Lifestyle factors contribute to aggressive disease, survival, and cardiovascular risk and are reversible. There's a movement towards emphasizing the whole patient, mental health, cardiovascular health, reducing obesity, eating healthy diets, vaccinations to prevent other infectious diseases, and long term attention on bone and heart. What are the new tests that have recently become available for prostate cancer?

•New predictive biomarkers : predictive biomarkers to guide hormonal therapy in localized prostate cancer were developed using digital pathology and artificial intelligence.

•More testing for targeted treatments : Most men in the community are not getting any testing, especially in rural and urology practices. You should ask your doctor about getting both germline (normal tissue) and tumor testing, which can identify potential treatment options for you. For example finding a BRCA mutation through a liquid biopsy indicates likely responsiveness to PARP inhibitors. What are the treatments that have recently become available for prostate cancer?

•New drug combinations : For example, combining androgen receptor inhibitors (like abiraterone) and PARP inhibitors (such as olaparib) for patients with metastatic castrate- resistant prostate cancer, especially for patients with a BRCA mutation, can block DNA repair and kill the cancer cells with overwhelming DNA mutations. Cancer cells often have faulty DNA repair, which can be encouraged by inhibiting the androgen receptor and the PARP enzyme. What are the treatments that are in the research phase for prostate cancer?

•Immunotherapy and other treatment combinations : Therapies leveraging the immune system have demonstrated huge successes in non-small cell lung, small cell lung, kidney, and bladder cancers. Researchers are trying to find similar results from combining immunotherapies with other treatment options in other cancers and developing ways to draw T-cells into tumors to overcome cancer recognition by the immune system.

•New treatments for neuroendocrine cancer : Neuroendocrine prostate cancer, a rare and aggressive form of prostate cancer, needs more research and advocacy to improve treatment options. Research on immunotherapy and platinum-based chemotherapy for neuroendocrine prostate cancer is showing mixed results. Researchers are targeting neuroendocrine prostate cancer with unique cell surface receptors (like bombesin). It's the first time it's ever been done. 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 patients, parp inhibitor, study, prostate cancer, combinations, therapy, ar, cancer, survival, inhibitors, men, metastatic, mutations, trial, years, questions, metastases, delay, african ancestry, progression SPEAKERS Andy Armstrong (87%), Brad Power (9%), Allen Morris (2%), John Sandiford (1%), David Plunkett (<1%). OUTLINE 1.Prostate cancer research and treatment. (0:03) 2.Prostate cancer treatment advancements and clinical trials. (1:12) 3.Prostate cancer treatment strategies and survivorship. (7:08) 4.Prostate cancer therapies and DNA repair. (11:58) 5.PARP inhibitors for prostate cancer treatment. (17:17) 6.Prostate cancer treatment options and research. (22:41) 7.Prostate cancer therapies and clinical trials. (26:58) 8.Prostate cancer treatment strategies and nomograms. (33:27) 9.Developing prostate cancer survival models. (38:52) 10.Prostate cancer treatment options and darolutamide efficacy. (43:57) 11.Personalized cancer treatment strategies. (48:28) SUMMARY

•Andy Armstrong shares more research and ideas on prostate cancer in a follow- up session.

•Andy Armstrong discusses prostate cancer research at Duke University, highlighting the use of potent AR inhibitors and multidisciplinary care for advanced disease.

•Armstrong presents findings on disparities in black men with aggressive prostate cancer, including unique outcomes from trials at Duke.

•Andy Armstrong discusses the latest advancements in prostate cancer treatment, including new combination therapies and the importance of early detection.

•He highlights the need for improved screening and early detection programs in emerging economies to reduce the prevalence of metastatic disease.

•Treatment intensification is now standard of care for prostate cancer, often involving potent AR blockers or triple therapy.

•Dr. Armstrong highlights the need for combined systemic therapy and radiation to improve prostate cancer outcomes.

•Andy Armstrong highlights the limited survival improvement of FDA-approved life-prolonging therapies for prostate cancer, with an average of 4-5 months of extra life.

•He advocates for comprehensive germline and tumor testing to identify potential treatment options for patients, including PARP inhibitors and liquid biopsy.

•He explains how combining AR and PARP inhibitors can lead to cancer cell death by overwhelming DNA repair errors.

•Andy Armstrong discusses a global study on metastatic castrate resistant prostate cancer patients, with a focus on the impact of PARP inhibitors on overall survival.

•The FDA approved the combination of abiraterone plus olaparib for patients with a BRCA mutation, as it showed a significant improvement in overall survival for this group.

•He discusses the benefits and risks of using PARP inhibitors in prostate cancer treatment, including delayed progression and anemia.

•Talazoparib, a new PARP inhibitor combination, shows promise in delaying progression, but has more anemia than other options.

•An expert oncologist is needed for careful dose reduction and monitoring to maximize benefit from radioligand therapy.

•Andy Armstrong discusses neuroendocrine prostate cancer, a rare and aggressive form of the disease, and the need for more research and advocacy to improve treatment options.

•Armstrong's institution is conducting research on immunotherapy and platinum- based chemotherapy for neuroendocrine prostate cancer, with mixed results.

•Andy Armstrong discusses prostate cancer research at the Alliance cooperative group, including new therapies and combinations of treatments.

•Armstrong highlights ongoing and upcoming trials, including a small molecule inhibitor of CXCR2 and a new AR degrader in conjunction with Celgene and BMS.

•Andy Armstrong discusses PARP inhibitors and their interactions with other drugs, highlighting the importance of dose reduction and drug combinations in cancer treatment.

•Drug combinations need randomized clinical trials to provide evidence for off- label prescriptions.

•Brad Power: Exploring more combinations to improve cancer treatment outcomes.

•Andy Armstrong: Combining immunotherapies with other treatments shows huge successes in non-small cell lung cancer, small cell lung cancer, kidney, and bladder cancer.

•He discusses developing ways to draw T cells into tumors to overcome cancer recognition by the immune system.

•Allen Morris asks how patients determine their prognosis in a metastatic castrate resistant state, with many permutations of patient pathways.

•Andy Armstrong discusses developing a nomogram for metastatic hormone- sensitive prostate cancer patients.

•He discusses the development of clinical genetic models for prostate cancer, which use a combination of clinical features and tumor genetics to predict survival rates.

•He explains that these models are intended to be communication tools between doctors and patients, providing estimates of survival rates that can inform treatment decisions.

•Andy Armstrong discusses targeting neuroendocrine prostate cancer with cell surface receptors like Bombesin, GPC3, somatostatin, and other targets.

•He highlights darolutamide as an equally active AR inhibitor to Enzalutamide, with advantages of less brain penetration and fewer side effects.

•Patient John Sandiford reports positive experience with darolutamide after 6.5 years of Lupron and docetaxel, with tolerability being a key factor in its selection.

•Andy Armstrong presents data on disparities in cancer treatment outcomes for black men, showing that they have better outcomes with immunotherapy than white men.

•A study at Duke found that intentionally including African American patients in a clinical trial (PANTHER) of apalutamide plus abiraterone in men with mCRPC which led to better outcomes for black men, with an 86% chance of making it to 5 years compared to 67% for white men.

•Andy Armstrong discusses the importance of inclusivity in cancer trials, with Brad Power acknowledging our weakness in including African American men in our community.

•Bob Gatenby is mentioned as a proponent of an adaptive intermittent approach to cancer treatment, which involves hitting the cancer hard and early, due to the heterogeneity of the population. Meeting

•For this coming year digital pathology is a big highlight. I talked about that last time.

•More impactful to patients who are trying to fight advanced or stag