Multi-omic Analysis Guides Advanced Prostate Cancer Treatment

•Advanced prostate cancer, diagnosed in 2016.

•Has had many tests over the years and has been through multiple lines of treatments including a radical prostatectomy, salvage radiation, six lines of systemic therapy, and two additional surgeries to remove metastatic lesions.

•Constriction of his right ureter (the tube that transports urine from the kidneys to the bladder) leading to kidney hydronephrosis (kidney swelling that happens when urine can't drain from a kidney and builds up in the kidney) and kidney damage, which affects his ability to pursue treatments that require full kidney function.

•Has had five operations since February 2023 to replace the ureter stent used to preserve as much kidney function as possible.

•In April 2024 the cancer spread to bone (typical for prostate cancer) in his spine (in the L2 vertebra, the second uppermost of the five lumbar vertebrae toward the lower end of the spinal column, within the lower back) leading to a compression fracture and spinal stenosis (the space inside the backbone is too small) requiring surgery to separate his spinal column from the spinal cord. He is recovering from that surgery.

•Suspended his most recent systemic therapy, a chemotherapy (docetaxel), in February to take a break from the side effects of a cytotoxic treatment.

•BostonGene completed extensive testing on Brian’s tumors in early 2024 and identified several targets to pursue. What did the BostonGene analysis uncover?

•Some alterations were uncovered from the latest biopsy sample (amplification of androgen receptor, and co-amplification of KIT/PDGFRA/VEGFR2, along with a PTEN gene mutation), suggesting evolutionary divergence and potential targets as the disease progresses.

•A transcriptomic (RNA) analysis looked for biomarkers that are valuable as antibody- drug conjugates (ADCs bind to the tumor cell, a chemical linker takes a cytotoxic drug inside the tumor cell, which kills the cancer cell while sparing healthy tissue.) for therapy (TROP2, Nectin4, and SLFN11), and all of these markers in both samples demonstrated a medium or a high level of RNA expression.

•RNA analysis also uncovered a medium or high level of expression of some other potential biomarkers ( HER2, HER3, and TGFb) . .

•The immune microenvironment has changed from an immune desert in Brian’s primary prostate sample to fibrotic in his metastatic sample.

•MxIF analysis revealed that a lot of the tumor cells demonstrate expression of synaptophysin (a specific and fairly sensitive marker for neuroendocrine tumors of both low and high grades of malignancy) and in the metastatic sample near 38%, and only 3% expression in the primary sample. What are the treatment options being considered for Brian?

•Chemotherapies: Brian’s synaptophysin (neuroendocrine marker) points to platinum therapies (such as carboplatin) and cabazitaxel.

•Targeted drugs: Drugs targeted at his gene mutations (e.g., VEGF and HER2), especially targeting the VEGF expression (KIT/PDGFRA/VEGFR2) with a tyrosine kinase inhibitor (cabozantinib) combined with an immune checkpoint inhibitor (nivolumab/Opdivo), which increases the efficacy over cabozantinib alone

•Antibody drug conjugates : to target Brian’s RNA biomakers (TROP2, NECTIN4, and HER2)

•AR (androgen receptor) degraders (a type of drug which interacts with the androgen receptor to downregulate this hormone activity, which feeds prostate cancer)

•Radionuclides (drugs that contain radiation that bind to tumor targets) : Alpha particle radionuclides (like actinium) are possible, but beta particle radionuclides (like Pluvicto) are not because of Brian’s kidney obstruction, which would hold the radiation in his kidneys for too long. (Actinium is not processed through the kidney.) What are the strategic principles being applied to make a decision on Brian’s next treatment?

•Outcome Goals: Consider two main outcome goals: quality of life and delaying disease progression.

•Integrate: Balance and integrate data from the research and the test reports, considering patient history, current treatments and clinical context when interpreting reports.

•Target: Identify specific vulnerabilities in the tumor (VEGF, angiogenesis signature – formation of new blood vessels in cancer growth) and insights on the disease (neuroendocrine) to target with drugs. Consider possible agents and their compatibility with other agents.

•Immune system: Prefer immunotherapy over chemotherapy to maintain the strength of the immune system.

•Safety: Look at FDA approval evidence in other cancers and where there is evidence of safety and efficacy in prostate cancer. Avoid drug combinations that have high toxicity risks (such as two VEGF drugs).

•Access: Favor treatments with easy access.

•Plan ahead: Keep treatments in reserve for future rounds and allow for new, better therapies to come to market.

•Validate: Validate the test results and findings: If decisions are being made based on the increased expression of synaptophysin, VEGF pathway, etc. and these decisions are based on a single data point/test (there is a confidence risk for RNA expression tests.), consider confirmation through other tests, such as (in order of decreasing confidence): (1) confirmation by IHC (immunohistochemistry - tissue staining) or a proteomic test, (2) a biological replicate showing the same signature (confirms the expression but does not unambiguously demonstrate a corresponding protein expression), and (3) molecular matching to similar patients who have shown increased expression and translation of the gene of interest.

•Disease burden: Keep the disease burden as low as possible. What is Brian’s next treatment going to be? Brian is planning to get a drug (cabozantinib) for inhibition of one of his biomarkers (VEGF) combined with an immunotherapy drug (nivolumab, brand name Opdivo, an immune checkpoint inhibitor). This combination has shown good efficacy in other cancers. Brian hopes to access this combination through a clinical trial being offered at UCSD. What are Brian’s next steps?

•Procure nivolumab and cabozantinib for his treatment, either through a clinical trial or, if he fails the eligibility criteria, through patient assistance programs.

•Monitor his response to treatment and disease progression through various tests, including scans, PSA (prostate-specific antigen blood test), radiographic progression, blood tests for molecular changes and assessments of his symptoms and quality of life. PSA is a tricky marker to follow in castrate-resistant prostate cancer, especially with AR (androgen receptor) amplification and it's not as reliable as in metastatic hormone- sensitive settings. There are several ways to monitor disease progression with blood draws, using various approaches (e.g., minimum residual disease testing), such as fragmentomics, which looks at fragmentation patterns of cell-free DNA from a blood draw and identifying interesting markers (such as DLL3, a ligand highly expressed in neuroendocrine tumors, and STEAP, a prostate-specific cell-surface antigen highly expressed in human prostate tumors). What can you learn from Brian that you can apply to your own care?

•Get an extensive diversity of tests to examine your cancer from different perspectives over time.

•Choose a quarterback for your care who is well-versed in the research and connected with you. (It may be hard to find medical oncologists like Dr. McKay who are willing or able to integrate complex molecular testing data into their practice). 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 brian, tumor, therapy, report, patient, sample, mckay, cancer, target, data, prostate cancer, psa, analysis, drugs, question, carbo, agents, inhibitor, gene, amplification SPEAKERS Rana McKay (42%) , Brian McCloskey (22%) , Kirill Kryukov (15%) , Brad Power (5%), Allen Morris (5%), Rick Davis (4%), Jonathan Starr (4%) , Kaumudi Bhawe (1%) , Saed Sayad (1%) SUMMARY Brian McCloskey shared his personal experience with cancer and Dr. Rana McKay provided an in-depth analysis of his cancer genomics. She presented a personalized treatment plan for Brian, combining VEGF inhibition with immunotherapy. The team discussed the potential synergies between different immunotherapies and emphasized the importance of delaying progression and enhancing the quality of life for patients undergoing cancer treatment. Later, the speakers discussed the potential of precision medicine in prostate cancer treatment, highlighting the importance of transcriptomic analysis, personalized treatment strategies and intelligent drug selection. Kirill Kryukov presented BostonGene’s analysis of Brian’s case, demonstrating the power of transcriptomic analysis in identifying key biomarkers. Dr. McKay discussed her interpretation of the test results and considerations of various therapeutic approaches. OUTLINE Prostate cancer treatment and research with patient Brian McCloskey.

•Brian McCloskey shares his cancer journey and introduces the topic of multi-omic insights.

•He expresses gratitude towards Dr. McKay for her exceptional care and support during a recent medical emergency. Dr. McKay has been Brian's doctor since 2017 and has been a source of comfort and strength throughout his cancer journey.

•He shares his cancer journey, including multiple systemic therapies and how BostonGene analyzed his cancer progression.

•Kirill Kiurkov of BostonGene will discuss multi-omic analysis and its implications for cancer treatment, followed by Rana's discussion of clinical implications. Cancer analysis, including gene mutations and immune system changes.

•Brian McCloskey and Kirill Kiurkov discuss analysis of Brian’s primary and metastatic tumor samples, revealing alterations in androgen receptor and kit genes.

•Kirill Kiurkov highlights medium/high RNA expression in both samples, including potential biomarkers like TGF beta.

•He analyzes Brian’s immune system and proposes treatment options based on findings. Targeted therapies for prostate cancer based on RNA sequencing report.

•Dr. McKay highlights the striking angiogenesis (the process of new blood vessels forming from existing blood vessels in the body) signature and multiple dysregulated VEGF pathway genes in prostate cancer.

•VEGF inhibition and immunotherapy combination shown to be effective in prostate cancer.

•She discussed potential treatment options for prostate cancer patient Brian, including “Nivo Cabo” (nivolumab plus cabozantinib). Personalized cancer treatment strategies based on the patient's genetic data and clinical context.

•Dr. McKay explained how they analyzed omics data to develop an IO therapy (immunotherapy) for Brian's cancer.

•She discussed the use of single-cell analysis and bulk RNA sequencing to understand Brian's tumor.

•She provided additional context on the combination of Cabozantinib and immunotherapy, citing FDA approval and potential underlying mechanisms.

•She explained that their strategy involves integrating data from reports with patient information to create personalized treatment plans.

•She highlighted the importance of considering patient history, current treatments, and clinical context when interpreting reports. Cancer treatment options for Brian, including immunotherapy and targeted therapy.

•Brian McCloskey shares his personal experience with cancer treatment and the importance of patient-clinician relationships.

•Dr. McKay explains how VEGF inhibitors and immunotherapy are used to treat cancer.

•She discusses the goal of therapy as delaying progression and maintaining quality of life. Cancer treatment options for Brian, including treatments targeted to his cancer profile and radioactive particle drugs (theranostics, radioligands).

•Brian McCloskey wants to find a drug that preserves his quality of life while slowing cancer progression.

•Precision medicine can help identify a specific vulnerability in the tumor to target with drugs.

•Dr. McKay explains that PSA is a tricky marker to follow in CRPC, especially with AR amplification, and it's not as reliable as in metastatic hormone-sensitive settings.

•She monitors multiple factors beyond PSA, including symptoms, radiographic progression, and response to therapy, to make treatment decisions.

•She discusses the limitations of theranostics (compounds that contain radiation and that bind to specific tumor targets in the body) in treating Brian’s kidney obstruction, which would hold the radiation in his kidneys for too long, highlighting the need for practical considerations in drug selection.

•Participants discuss the potential of new radioactive agents, including actinium and PSMA, for castration-resistant prostate cancer treatment. Prostate cancer treatment options, including neuroendocrine and AR- targeted therapies.

•Rick Davis expresses concern about potential neuroendocrine cancer and asks about treatment options.

•Dr. McKay discusses the challenges of defining neuroendocrine prostate cancer, including controversy around the use of IHC markers.

•She mentions the potential opportunity for Brian to participate in a degrader study for AR-mutated tumors.