Therapy For Metastatic Prostate Cancer Research Articles

2023 expert consensus on decision pathway of metastatic hormone-sensitive prostate cancer management in Taiwan

This short communication presents a consensus-based expert opinion from a multidisciplinary team of Taiwanese experts in urology, medical oncology, and radiation oncology regarding the management of metastatic hormone-sensitive prostate cancer (mHSPC). Through a comprehensive review of recent clinical trials examining the efficacy of novel hormonal agents (NHAs) and docetaxel, alongside updated guidelines for mHSPC management, the experts have deliberated on the practical implications from currently available literatures. The discussion focused on the combination of androgen deprivation therapy, NHAs, and docetaxel, as reported in the leading studies including ARASENS (ODM-201 in Addition to Standard ADT and Docetaxel in Metastatic Castration Sensitive Prostate Cancer), ENZAMET (Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer), and PEACE-1 (A Phase III Study for Patients with Metastatic Hormone naive Prostate Cancer) trial. The risk-benefit ratio between prolonged overall survival and the incidence of major adverse events was thoroughly evaluated. This consensus underscores the recommendation that early initiation of intensified triplet therapy with docetaxel, NHA, and androgen deprivation therapy is beneficial for fit mHSPC patients with highly aggressive disease characteristics, effectively prolonging overall survival with manageable risk of adverse events.

Patient preferences for metastatic prostate cancer treatment: a discrete choice experiment

BackgroundTo examine the preference weightings for risk/benefit attributes of therapy in metastatic prostate cancer(mPC) patients, encompassing hormone-sensitive(mHSPC) and castration-resistant(mCRPC) settings. Patients and MethodsA non-interventional cross-sectional survey employing a discrete choice experiment was conducted, recruiting 200 mHSPC and 100 mCRPC patients within 5 years of diagnosis from the urology and oncology specialty clinics between Feb 2023 and Jul 2023. Patients were randomized into 2 blocks of 9 questions, choosing 1 out of 2 medication profiles consisting five attributes, each with 3 levels, determined from a group interview of 5 patients. A mixed logit model estimated attribute-level preference weightings, with tradeoff points calculated. ResultsMedian age was 75(IQR:71-81), 170(56.7%) had no income, 245(81.7%) cared for themselves, mean maximum out-of-pocket treatment cost was US$20,456(SD:43,568), and 160(53.3%) claimed not to consider further treatment when cost exceeding their affordability. Patients favoured self-care ability(4.37,P<.001) and life expectancy extension(2.83,P<.001), disfavoured adverse effects (-6.97,P<.001) and treatment cost(in HK$million or USD$128,205)(-3.14,P<.001). mCPRC patients was more sensitive to treatment cost(-3.61vs-2.97), life expectancy extension(3.47vs2.55) and adverse effects(-7.55vs-6.80) compared to mHSPC patients. Higher financial affordability patients exhibited higher sensitivity to self-care ability(4.89vs4.02) and adverse effects(-7.57vs-6.70). ConclusionThe chance of adverse effects was pivotal in treatment decisions, followed by self-care ability, with cost remaining a major access barrier. Micro AbstractExamining the preference weightings for risk/benefit attributes of therapy in metastatic prostate cancer patients, we recruited 200 hormone-sensitive and 100 castration-resistant patients for a cross-sectional discrete choice experiment survey. A mixed logit model estimated attribute-level preference weightings, calculating tradeoff points. The chance of adverse effects and self-care ability were pivotal in treatment decisions, with cost remaining a major access barrier.

Evaluating the Importance of Practice-Level Factors on Adherence to Prostate Cancer Treatment Guidelines in Urology

ObjectiveTo evaluate adherence to treatment guideline recommendations across the continuum of prostate cancer care by US community urologists using several prostate cancer (PCa) specific performance indicators (PIs). Additionally, to determine which practice-related factors, such as having a designated PCa patient champion, active patient management in a patient portal, and in-office dispensing of medications, were associated with improved PI performance. MethodsElectronic medical record data was collected retrospectively from the PPS Analytics Patient Population Health Management Platform. The cohort consisted of adult patients with a PCa-related service visit during the period 7/1/2019 to 6/30/2022. Five PIs were reviewed: dual-energy x-ray absorptiometry (DEXA) scanning with androgen deprivation therapy (ADT), systemic therapy in metastatic PCa, external beam radiation therapy (EBRT) concurrent with ADT, image monitoring, and regular testosterone testing and monitoring. ResultsA total of 101,186 patients were identified from 95 urology practices. PI adherence rates ranged from a low of 13.6% for a DEXA scan within 6-months of ADT initiation to a high of 72.3% for EBRT concurrent with ADT in intermediate/high risk localized PCa. The results also demonstrated that several practice-related features were associated with better PI adherence. ConclusionsThe findings suggest there exists a wide range in PI adherence rates for urologists in the delivery of community urology care in the Unites States compared to clinical guideline recommendations. Future research should examine the factors associated with PI nonadherence and promote implementation of interventions that enhance guideline concordant care.

Evaluation of guideline recommended treatment utilization among Black and White men with metastatic prostate cancer.

103 Background: Prostate cancer is the second leading cause of cancer death among men with a disproportionate burden on Black men. 1 Black men are twice as likely to die from prostate cancer compared to White counterparts. 2 Racial disparities in care delivery for early-stage disease are well documented and may contribute to disparate outcomes, 3–6 but less is known about racial gaps in advanced prostate cancer care, a stage where effective therapies can prolong life for years. 7 We sought to evaluate if treatment disparities were evident among Black and White men with metastatic prostate cancer. Methods: We performed a retrospective cohort study of patients with metastatic prostate cancer receiving treatment at a large public tertiary care health system between 2015 and 2020. Demographic, clinical, treatment, and medication prescribing data were extracted from the electronic health record. We excluded patients without ICD codes indicating metastatic disease, those without any documented medication data in our health system, and those who did not identify as Black or White race. We estimated the prevalence ratio (PR) of being prescribed each of the recommended treatment options for metastatic prostate cancer per National Comprehensive Care Network guidelines, including androgen deprivation therapy (ADT), novel anti-androgens, chemotherapy, and bone protection comparing Black men to White men using log-binomial regression. Results: We identified 1,594 patients with metastatic prostate cancer; 485 (30%) were Black. Black patients were younger and had higher Charlson scores compared to White men. Both groups were highly insured, Medicaid was more common for Black men (7.2% vs 2.2%). Prescribing of systemic treatments was similar by race (Table). Combination ADT and novel antiandrogen prescribing was also similar by race (PR 1.04 95% CI:(0.91 - 1.17), p=0.6). About 30% of both Black and White patients interacted with our Patient Navigation team, a group of oncology nurses focused on ensuring patients receive recommended care. Conclusions: In a large public tertiary care health system, we did not observe racial disparities in receipt of guideline recommended therapies for metastatic prostate cancer. High rates of insurance, a robust patient navigation program, and a well-developed pharmacy assistance program may have helped mitigate racial disparities in care. Ongoing analyses are evaluating prescribing patterns among patients with de novo metastatic disease. Future studies should explore delivery of prostate cancer therapies across health systems and the influence of patient navigation and pharmacy assistance programs on medication receipt. Prevalence ratios of treatment by race. Medication PR (95% CI) for Black v White men p-value ADT 1.04 (0.98-1.11) 0.19 Novel Antiandrogen 1.05 (0.95-1.16) 0.31 Bone protection 0.89 (0.76-1.04) 0.13 Chemotherapy 1.09 (0.85-1.39) 0.51

Abstract C098: CYR61 expression in prostate cancer patients at City of Hope

Abstract In the US, African-American (AA) and Hispanic/Latino (H/L) men have higher rates of advanced prostate cancer (PCa), increased PCa-specific mortality, and are more likely to undergo metastasis than non-Hispanic White (NHW) men attributed to a lack of access to early screening, and a higher prevalence of risk factors such as obesity, diet, and genetic differences. Consequently, effective treatment of advanced PCa and elimination of racial and ethnic disparities for this malignancy require the identification of mechanisms of disease progression. In PCa, the cysteine-rich angiogenic inducer 61 (CYR61) contributes to malignant cell growth through interactions with extracellular ligands, such as integrins avb3 and a6b4. In previous studies, we have found that CYR61 is upregulated in metastatic PCa cell lines and knockdown of this protein significantly reduced metastatic cell proliferation, viability, prostasphere formation, and activation of the PI3/AKT pathway, indicating a potential utilization of CYR61 inhibition in the therapy of metastatic PCa. Interestingly, we have observed that in metastatic PCa cell models, IGF1 induction increased CYR61 protein expression. However, the correlation between PCa aggressiveness and levels of CYR61 in tumor-derived tissues from patients is poorly studied. Our goal with this study is to identify possible correlations in CYR61 expression that may reflect health disparities in PCa outcomes. We used in silico analyses from whole exome paired tumor/normal DNA sequencing and tumor RNA sequencing data available on 542 PCa cases in the City of Hope POSEIDON database to determine whether gene expression of CYR61 and IGF1 was correlated with genetic ancestry, Gleason score, and tumor purity. In univariate analyses, we found that H/L PCa cases had significantly higher levels of expression of CYR61 than NHW PCa cases (p = 0.043) and that both H/L and AA PCa cases had higher IGF1 expression levels, although only significant in AA (p=0.031). We also found that PCa patients with Gleason scores of 8 and higher had significantly lower expression of IGF1 than those with Gleason scores of 7 or less (p=0.006). Both CYR61 and IGF1 expression levels were significantly lower in those with luminal B (p=0.00000000053, p=0.000009, respectively) and with basal subtypes (p=0.00035, p=0.000069, respectively compared to luminal A subtype. Tumor purity was estimated by RNA-seq based on 141 genes specific to stroma and 141 genes specific to immune cells. CYR61 expression was significantly correlated with stromal and immune infiltration. These results suggest that reduced CYR61 expression is associated with more aggressive PCa. Additional analyses are ongoing to understand the interplay of variables of race and ethnicity, age, Gleason score, and tumor purity and to investigate outcomes of biochemical recurrence and death from PCa. Citation Format: Greisha L. Ortiz-Hernandez, Yuan Chun Ding, Susan L. Neuhausen. CYR61 expression in prostate cancer patients at City of Hope [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C098.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Prescription Medications and Overall Survival in Metastatic Hormone Sensitive Prostate Cancer.

With new therapies for metastatic prostate cancer, patients are living longer, increasing the need for better understanding of the impact of comorbid disease. Prescription medications may risk-stratify patients independent of established methods, such as the Charlson Comorbidity Index (CCI) and guide treatment selection. In a nationwide retrospective study of US Veterans, we used multivariable logistic regression and Cox proportional hazard modeling to evaluate the association between number and class of prescription medications and overall survival (OS) with age, race, body-mass index, prostate specific antigen (PSA), and Charlson comorbidities as covariates in veterans treated for de novo metastatic hormone sensitive prostate cancer (mHSPC) between 2010-2021. Among 8,434 Veterans, a median of nine medications and five medication classes were filled in the year prior to initial treatment with abiraterone or enzalutamide for mHSPC. Veterans on 1-4 medications had an average survival of 38 months compared to 5-9 medicines (33 months), 10-14 medicines (27 months), and 15+ medicines (22 months) (p<0.001). After adjusting for age, race, body mass index (BMI), PSA, CCI, and year of diagnosis, both the number of medications and medication classes were associated with increased mortality. The adjusted hazard ratio (aHR) [95% confidence interval (CI)] was 1.03 (1.02-1.03) for the number of medications and 1.05 (1.04-1.07) for medication classes. Medications within ATC B (blood/blood forming organs), ATC C (cardiovascular), and ATC N (nervous) were associated with worse OS, with aHRs of 1.14 (1.07, 1.21), 1.14 (1.06, 1.22), and 1.12 (1.06, 1.19), respectively. The number and class of medications were independently associated with overall survival in patients undergoing treatment for mHSPC. With new therapies for advanced prostate cancer, patients are living longer, highlighting the need for a better understanding of the impact of comorbid diseases. Simple methods to assess disease burden and prognosticate survival have the potential to guide treatment decisions.

Towards personalized patient 3D Monte Carlo dosimetry for Lu-177-psma prostate treatments

Prostate-Specific Membrane Antigen (PSMA)-labeled Lu-177 therapy is a novel nuclear medicine therapy for metastatic prostate cancer, increasingly adopted worldwide due to the benefits observed in different patient studies. Administered in several cycles, each with a single injection and with a standard activity, the therapy requires customized dosimetry to evaluate efficacy and toxicity. The uptake of Lu-177-PSMA-617 in different organs strongly depends on the patient's anatomy, metastasis distribution, and the activity injected, underscoring the need for personalized dosimetry. This study aims to conduct dosimetry research on patients after several cycles of Lu-177-PSMA administration by Monte Carlo simulation using MCNP6.2. In order to make this study as realistic as possible, a high-resolution anthropomorphic computational phantom is used, the “Mesh-type Reference Computational Phantom” (MRCP) described in ICRP publication 145. This methodology is applied to different distributions of metastatic tissue, based on SPECT images where activity distribution within the patient's body is localized. Since Lu-177-PSMA-617 is deposited in those regions where prostate cancer metastasis has occurred, in Monte Carlo simulations these organs are considered as a source of irradiation with different emission activities probabilities depending on the patient. Once the organ activity distribution is determined, the simulation is performed in MCNP6.2 and the 3D dose distribution in the phantom is evaluated. Based on Monte Carlo results, doses at organs at risk are evaluated, estimating the total absorbed doses until the complete disintegration of Lu-177.Simulation results enable personalized adjustment of injected Lu-177 according to the needs of the clinical case. This approach has proven to be a valuable tool for assessing individual patient doses, treatment effectiveness, and healthy organ irradiation levels.

Combination of miR-99b-5p and Enzalutamide or Abiraterone Synergizes the Suppression of EMT-Mediated Metastasis in Prostate Cancer.

Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer deaths among American men. Androgen deprivation therapy (ADT) has been systemically applied as a first-line therapy for PCa patients. Despite the initial responses, the majority of patients under ADT eventually experienced tumor progression to castration-resistant prostate cancer (CRPC), further leading to tumor metastasis to distant organs. Therefore, identifying the key molecular mechanisms underlying PCa progression remains crucial for the development of novel therapies for metastatic PCa. Previously, we identified that tumor-suppressive miR-99b-5p is frequently downregulated in aggressive African American (AA) PCa and European American (EA) CRPC, leading to upregulation of mTOR, androgen receptor (AR), and HIF-1α signaling. Given the fact that mTOR and HIF-1α signaling are critical upstream pathways that trigger the activation of epithelial-mesenchymal transition (EMT), we hypothesized that miR-99b-5p may play a critical functional role in regulating EMT-mediated PCa metastasis. To test this hypothesis, a series of cell biology, biochemical, and in vitro functional assays (wound healing, transwell migration, cell/ECM adhesion, and capillary-like tube formation assays) were performed to examine the effects of miR-99b-5p mimic on regulating EMT-mediated PCa metastasis processes. Our results have demonstrated that miR-99b-5p simultaneously targets MTOR and AR signaling, leading to upregulation of E-cadherin, downregulation of Snail/N-cadherin/Vimentin, and suppression of EMT-mediated PCa metastasis. MiR-99b-5p alone and in combination with enzalutamide or abiraterone significantly inhibits the EMT-mediated metastasis of AA PCa and EA CRPC.

Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis.

Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC. PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models. Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification. Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.

Clinical Management of Advanced Prostate Cancer: Where Does Radiopharmaceutical Therapy Fit in the Treatment Algorithm?

Most men with newly appreciated metastatic prostate cancer are optimally treated with a backbone consisting of androgen receptor-directed therapy with or without taxane chemotherapy. Despite improvements in disease outcomes, prostate cancer remains an extremely heterogeneous disease with variable mechanisms of therapeutic resistance. As a result, it remains a leading cause of cancer-related death in men. Radiopharmaceutical therapy has emerged as an alternative, non-androgen receptor-directed treatment modality for metastatic castration-resistant prostate cancer that impacts patient survival and represents a potentially more personalized approach. In this review, we aim to outline the current treatment landscape for metastatic prostate cancer with a focus on radiopharmaceutical therapy, specifically 177Lu-PSMA-617. In addition, we illustrate various clinical challenges with 177Lu-PSMA-617 treatment to date and explore investigative efforts to leverage radiopharmaceutical therapies as part of combination regimens or earlier in the treatment algorithm to further improve patient outcomes. Finally, we introduce ongoing studies of alternative radiopharmaceutical therapies in metastatic prostate cancer that may be incorporated into the treatment algorithm pending further study.

Current clinical application of lutetium‑177 in solid tumors (Review).

Radionuclide-based therapy represents a novel treatment regimen for tumors. Among these therapies, lutetium-177 (177Lu) has gained significant attention due to its stability and safety, as well as its ability to emit both γ and β rays, allowing for both imaging with single photon emission computed tomography and tumor treatment. As a result, 177Lu can be used for both diagnosis and treatment for diseases such as prostatic and gastric cancer. Therefore, based on the available data, the present review provides a brief overview of the clinical applications of 177Lu-targeted radionuclide therapy in metastatic prostate cancer, neuroendocrine tumors and other types of solid tumors, and highlights the current therapeutic effect, reduction in damage to normal tissues and future research directions, including the development of new nuclides and the application of more nuclides in different tumors. In the future, such treatments could be used in more tumors.

Abstract 5967: Blockade of Wnt5A/ROR1 signaling as cancer stem cell targeting therapy for metastatic prostate cancer

Abstract BACKGROUND– Wnt5A and its non-canonical Wnt receptor, ROR1, have emerged as a promising new signaling pathway target for lethal, metastatic prostate cancer. Wnt5A has emerged as a significant marker of poor prognosis in circulating tumor cells (CTCs) of metastatic castration resistant prostate cancer (mCRPC) patients. ROR1 is expressed in lethal types of mCRPC, especially neuroendocrine prostate cancer (NEPC). A therapeutic ROR1 antibody, Zilovertamab, has been clinically tested in chronic lymphocytic leukemia (CLL) and metastatic breast cancer and shown to be safe. We sought to investigate Zilovertamab-based therapies for metastatic prostate cancer in pre-clinical model systems. HYPOTHESIS – Wnt5A/ROR1 signaling may mediate a cancer stem cell program which makes cells resistant to therapies which target the cell cycle and proliferation. Blocking ROR1 may reveal vulnerabilities which sensitize cancer cells to chemotherapies like docetaxel. METHODS– ROR1 expression was determined using RNASeq, qRT-PCR, FACS, IHC and Western blotting. ROR1 signaling was blocked using the anti-ROR1 therapeutic antibody, Zilovertamab, or CRISPRCas9 ROR1 knock out. Cell growth was measured using an Incucyte real time imaging system. Stem cell activity was assessed in 3D organoids. Cell cycle analysis was performed in live cells in 2D cultures and 3D organoids using the Fucci2BL bicistronic Fluorescent, Ubiquitination-based Cell Cycle Indicator reporter system. PDX PCSD13 tumor growth was measured via calipers and IVIS. RNASeq was performed on tumors. RESULTS– We showed that ROR1 was expressed at high levels in mCRPC cell lines: PC3, DU145, and in the bone metastatic prostate cancer PDX: PCSD13. CRISPR/Cas9 Knock out of ROR1 in PC3 and DU145 cells showed increased sensitivity to docetaxel inhibition of proliferation in vitro in 2D real time Incucyte proliferation assays and in 3D organoids. Organoid formation was significantly reduced in ROR1 KO cells. Cells expressing the FUCCI live cell cycle tracker showed docetaxel led to G2 arrest and ROR1 signaling inhibition increased efficacy of docetaxel induced cell cycle arrest. Treatment of PCSD13 PDX in vivo with Zilovertamab plus docetaxel synergistically increased tumor growth inhibition in vivo and modulated cancer stem cell and cell cycle expression profiles. CONCLUSIONS– Cancer stem cells represent the fundamental precursors from which all diverse tumor subpopulations evolve. Thus, therapeutic targeting of these tumor initiating stem/progenitor cells may prevent the evolutionary diversification of a tumor and overcome a critical clinical barrier to cancer treatment. We showed synergistic response in our PDX and PCs cell line models to Zilovertamab plus docetaxel. We are now conducting a phase 1b clinical trial with zilovertamab plus docetaxel in patients with metastatic CRPC (CirmD, NCT05156905, PI R Mckay). Citation Format: Christina A.M. Jamieson, Jamillah Murtadha, Christopher S. Oh, Michelle T. Muldong, Niloofar Etemadfard, Evodie Koutouan, Young E. Yoon, Sanghee Lee, Oh Kwon, Jong J. Oh, Min S. Kim, Karl Willert, Nicholas A. Cacalano, Catriona H.M. Jamieson, Terry Gaasterland, Rana R. Mckay, Christopher J. Kane, Anna A. Kulidjian, Charles E. Prussak. Blockade of Wnt5A/ROR1 signaling as cancer stem cell targeting therapy for metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5967.

Abstract 3036: Sensitivity of ONC201/TIC10 cancer therapeutic on neuroendocrine prostate cancer (NEPC) and neuroendocrine differentiation (NED)

Abstract Although androgen deprivation therapy and androgen receptor (AR) blockade are highly effective therapies for metastatic prostate cancer (PCa), most patients develop resistance, leading to castration-resistant prostate cancer (CRPC). A subset of CRPC shows neuroendocrine prostate cancer (NEPC) features, which are associated with poor prognosis and limited therapeutic strategies. NEPC is characterized by oncogenic driver activation and epigenetic changes, partly controlled by transcription factors like BRN2 and SOX2. AR has been shown to suppress BRN2 transcription, which is required for NEPC, and BRN2-dependent regulation of the NEPC marker SOX2 (Bishop et al., 2017). Dordaviprone (ONC201/TIC10) is a first-in-class small molecule that antagonizes DRD2, induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and activates the integrated stress response (ISR). Neuroendocrine tumors express significant DRD2 levels, suggesting ONC201 as a potential therapeutic strategy in NEPC or when drivers for disease progression are overexpressed (OE). PCa cell lines PC3, DU145, LNCaP, and 22RV1 are ONC201 sensitive, with IC50=2.87 μM, 3.18 μM, 1.31 μM, and 1.16 μM, respectively (Ding et al., 2023). To characterize the association of BRN2/SOX2 dysregulation with ONC201 sensitivity, we transiently OE BRN2/SOX2 in PCa. We hypothesized that markers of neuroendocrine differentiation (NED), activation of the ISR, TRAIL, and ClpP and dopamine receptor expression contribute to NEPC cell death and sensitivity to ONC201. We performed CellTiter-Glo experiments to assess viability after 96 hours ± BRN2 OE. DU145 cells with BRN2 OE increased their sensitivity to ONC201 (IC50=2.75 µM) compared to empty vector (IC50=3.03 µM). Colony formation assays were conducted in PCa and analyzed 7 days after ONC201 treatment to show ONC201 effect on PCa cell lines. DU145 was treated at 0.5, 1, and 2 µM of ONC201. There were 95 ± 3.22 colonies for the control group, 83 ± 5.22 colonies with 0.5 µM, 74 ± 3.64 colonies with 1 µM, and 8 ± 2.03 colonies with 2 µM ONC201. DU145 showed a significant reduction in colony-forming ability when treated with 1 and 2 uM ONC201 compared to the control, with P values of &amp;lt;0.05 and &amp;lt;0.0001, respectively. We OE BRN2 and observed changes in NED markers and ISR pathway. In PC3, FoxO1 and ATF4 levels increased. In DU145, FoxO1, ENO2, PGP9.5, CgA, and ATF4 levels decreased. We reveal that DU145 OE at 48 hours does not result in greater expression of NEPC markers. BRN2 OE significantly increased PCa cell sensitivity to ONC201 and was evident without an increase in common phenotypical markers used for NEPC assessment (FoxO1, ENO2, PGP9.5, CgA). Expression change was not shown when PCa had an integral AR pathway. Ongoing efforts are observing ONC201 treatment effects on NED markers and the TRAIL pathway due to BRN2 OE and showing increased sensitivity of PCa to ONC201 with BRN2 OE. Citation Format: Elizabeth C. Ding, Maximilian Pinho-Schwermann, Shengliang Zhang, Connor Purcell, Wafik S. El-Deiry. Sensitivity of ONC201/TIC10 cancer therapeutic on neuroendocrine prostate cancer (NEPC) and neuroendocrine differentiation (NED) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3036.

Abstract 560: IGF1 induces the expression of CYR61 in metastatic prostate cancer

Abstract The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. Interestingly, CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of CYR61-IGF1 interaction to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. In conclusion, these data provided evidence that CYR61 expression is induced by IGF1, and its inhibition decreased the capacity of metastatic PCa cells to proliferate, indicating a potential utilization of CYR61 inhibition in the therapy of metastatic PCa. Citation Format: Greisha L. Ortiz Hernandez, Mya Walker, Leanne Woods-Burnham, Rick A. Kittles, Carlos A. Casiano, Susan Neuhausen. IGF1 induces the expression of CYR61 in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 560.

Lutetium-177 Labelled Anti-PSMA Monoclonal Antibody (Lu-TLX591) Therapy for Metastatic Prostate Cancer: Treatment Toxicity and Outcomes.

Whilst prostate cancer is the fourth most common cancer globally, effective therapies for patients with advanced disease are lacking. In recent years, interest in using theranostic agents to treat castrate-resistant prostate cancer (CRPC) and metastatic prostate cancer has emerged. Lu-TLX591 monoclonal antibody is a potential agent of significance; however, to date, reports on its toxicity and efficacy have been limited to small clinical trials in heavily pretreated patients. This retrospective study describes the real-world toxicity and efficacy profile of Lu-TLX591. Eighteen patients received Lu-TLX591 at two private oncology centres in Australia. Patients were eligible if they had CRPC or metastatic prostate cancer and prostate-specific membrane antigen (PSMA)-avid disease confirmed by PSMA-positron emission tomography (PET). Patients received two cycles of Lu-TLX591 monoclonal antibody (177 Lu-DOTA-rosopatamab) each dosed from 1.01-2.85 GBq, 14 days apart. Patient side effects, blood test results and radiology reports were recorded on the patient's electronic medical record (eMR). Prominent side effects included fatigue (55.6%), anorexia (16.7%), nausea (11.1%), and transfusion reactions (11.1%). All-grade haematological toxicities included lymphopenia (61.1%), anaemia (22.2%), leukopenia (27.8%), neutropenia (27.8%), and thrombocytopenia (27.8%). Grade 4 toxicity included lymphopenia (6.7%) and thrombocytopenia (6.7%). Patients' prostate-specific antigen (PSA) responses were as follows; ≥ 30% PSA decline (27.8%), ≥ 50% PSA decline (11.4%) and any PSA decline (38.9%). Follow-up radiology revealed 54.5% stable disease, 45.4% disease progression and 9.1% disease regression. Lu-TLX591 was safely administered at acceptable toxicity and its efficacy reflects previous clinical trials. Larger studies are required and are underway (NCT04786847; NCT05146973; NCT04876651) to determine Lu-TLX591 effectiveness amongst different prostate cancer populations and compare its efficacy against peptide-based radiopharmaceutical agents.

Strength through unity: Alkaline phosphatase-responsive AIEgen nanoprobe for aggregation-enhanced multi-mode imaging and photothermal therapy of metastatic prostate cancer

Strength through unity: Alkaline phosphatase-responsive AIEgen nanoprobe for aggregation-enhanced multi-mode imaging and photothermal therapy of metastatic prostate cancer

Stereotactic ablative radiation therapy in metastatic prostate cancer.

The evolving role of stereotactic ablative radiation therapy (SABR) as metastasis-directed therapy (MDT) for oligometastatic prostate cancer (omPCa) will be discussed. Oligometastatic disease (OMD) is an intermediate state between localized and wide-spread malignant disease. OMD has recently been spotlighted given the increasing demonstration of clinical benefit from local therapies despite presence of metastatic disease and allure of the curative potential of MDT in select cases. Among the different forms of MDT, SABR has rapidly become a widely adopted treatment modality. Significant efforts in this space have focused on omPCa, owing to its relatively indolent biology, presence of a sensitive and specific serum biomarker and recent advances in molecular imaging. While most studies have evaluated the role of SABR MDT in hormone sensitive omPCa, new emerging clinical data also suggests benefits of SABR MDT for even castration-resistant disease. Treating omPCa with SABR MDT appears to generate an efficacy signal with minimal morbidity across both hormone-sensitive and castration-resistant disease. However, additional definitive omPCa trial data are needed. Future research efforts should investigate biomarkers for this heterogeneous disease space and the role of SABR MDT in combination with systemic agents to improve upon standard of care treatments.

A study to evaluate patient benefit/risk preferences for treatment of metastatic prostate cancer (mPC) in Hong Kong: A discrete choice experiment.

104 Background: The patient’s preference for treatment is dynamic across different cultures and at various stages of cancer. Yet little is known regarding their priorities in making treatment decisions. The study's primary objective is to examine the preference weightings in terms of risk/ benefit attributes of therapy in metastatic prostate cancer (mPC) patients in both the hormone-sensitive (mHSPC) and castration-resistant (mCRPC) settings. Methods: This is a non-interventional cross-sectional survey study. A discrete choice experiment was used to assess their priorities on treatment options. 300 consecutive patients with mPC (200 mHSPC and 100 mCRPC) diagnosed within 5 years were recruited from the specialty clinics of our hospital from Feb 2023 to Jul 2023. A facilitated group interview session of 5 patients was conducted to evaluate the importance and relevance of potential attributes selected from the literature search. Five attributes were adopted, and each has 3 levels compromised between real-life rates and expectations of patients from the interview session. Patients were randomized into 2 blocks by recruitment sequence and chose 1 medication profile out of 2 throughout the 9 questions in each block of the questionnaire. A mixed logit model was used for data analysis. Results: Median age was 75 (IQR:71-81). One hundred and seventy (56.7%) had no income, and 245 (81.7%) claimed to take care of themselves. The mean maximum amount affordable for treatment was US$20,456 (SD:43,568), and 160 (53.3%) said they would not consider further treatment if the cost exceeded their affordability. Compared to intravenous formulation, oral medication once/day had a non-statistically significant favorable preference (0.06 p:0.272), and oral medication twice/day had a negative statistically significant preference (-0.20 p:0.040). The percentage of retained self-care ability (4.37 p&lt;0.001) and percentage of extension in life expectancy (2.83 p&lt;0.001) had a statistically significant favorable preference. In contrast, the chance of adverse effects leading to complicated medication treatment or hospitalization (-6.97, p&lt;0.001) and treatment cost (in HK$ million) (-3.14 p&lt;0.001) had a negative statistically significant preference. The mCPRC group was more sensitive to changes in treatment cost (-3.61 vs. -2.97), percentage of extension in life expectancy (3.47 vs. 2.55) and the chance of adverse effects (-7.55 vs -6.80) than the mHSPC group. Those who could afford treatment were more sensitive to the percentage of retained self-care ability (4.89 vs. 4.02) and the chance of adverse effects (-7.57 vs -6.70) than those who could not. Conclusions: The chance of adverse effects took the largest weighting in treatment decisions, followed by the percentage of retained self-care ability.

Real-world genomic testing patterns in patients with prostate cancer.

97 Background: The armamentarium of therapies for metastatic prostate cancer (PCa) has now expanded to include genomically targeted agents and CPIs. Men with both somatic and germline alterations in the DNA damage repair (DDR) pathway, most commonly BRCA2, are candidates for PARP inhibitors. Recent data from the PROPEL and MAGNITUDE trials led to approval of PARP inhibitors in combination with novel hormonal therapies earlier in the PCa continuum, in the first-line metastatic castrate-resistant space. Some PCas harbor genomic alterations, such as TMB&gt;10 m/Mb and MSI high, which predispose to increased responses to CPIs, leading to tumor agnostic approval of pembrolizumab in these patient populations. However, it is imperative to perform timely genomic testing to assess for presence of these alterations. Methods: We conducted a 15-question survey using the Qualtrics XM software to assess genomic testing patterns of various providers in academic and community settings managing PCa patients. The survey link was distributed electronically to providers predominantly in the Western United States. Results: A total of 47 survey responses were received, with 59.6% (28/47) self-identifying as medical oncologists (Onc), 21.3% (10/47) as urologists (Uro), 4.3% (2/47) as radiation oncologists, 8.5% (4/47) as advanced practitioners, and 6.4% (3/47) as other. Academic Onc comprised 23.4 % (11/47), community Onc comprised 36.2% (17/47), academic Uro comprised 17.0% (8/47), and community Uro comprised 4.6 % (2/47) of providers. Timing of ordering of germline and somatic genomic testing by selected provider type is outlined in the Table. Conclusions: Given availability of targeted therapies in PCa management, ordering germline and somatic germline genomic testing is imperative. Despite the small sample size, several trends emerge from this dataset. Oncs at academic centers tend to order genomic testing earlier than Oncs at community practices, while Uros were less likely to order genomic testing when compared to Oncs in general. [Table: see text]