Hormone-sensitive Prostate Cancer Research Articles

Identifying Suitable Patients for Overcoming Androgen Deprivation Monotherapy in De Novo Metastatic Hormone-Sensitive Prostate Cancer

Identifying Suitable Patients for Overcoming Androgen Deprivation Monotherapy in De Novo Metastatic Hormone-Sensitive Prostate Cancer

Metastatic Hormone-Sensitive Prostate Cancer and Combination Treatment Outcomes

ImportanceMetastatic hormone-sensitive prostate cancer is currently an incurable disease. Despite a high response rate to androgen-deprivation therapy, most cases progress to castration-resistant disease, the terminal phase. This review provides a summary of the most recent evidence for current and emerging management strategies, including treatment intensification with combinations of therapies. It also provides recommendations on applying the evidence in clinical practice to encourage appropriate treatment to improve survival outcomes among patients with metastatic hormone-sensitive prostate cancer.ObservationsAndrogen-deprivation therapy is the backbone of treatment for metastatic hormone-sensitive prostate cancer; however, it is insufficient alone to provide sustained disease control and long-term survival. Addition of an androgen receptor pathway inhibitor and/or docetaxel significantly improves survival, as demonstrated by several international phase 3 randomized clinical trials. Triplet therapy composed of androgen-deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel has been shown to improve overall survival over androgen-deprivation therapy plus docetaxel. In the ARASENS trial (darolutamide), the hazard ratios (HRs) were 0.68 (95% CI, 0.57-0.80) in the overall population; 0.71 (95% CI, 0.59-0.85) and 0.61 (95% CI, 0.35-1.05) in patients with de novo and recurrent disease, respectively; 0.69 (95% CI, 0.57-0.82) and 0.72 (95% CI, 0.41-1.13) in patients with high-volume and low-volume disease, respectively; and 0.71 (95% CI, 0.58-0.86) and 0.62 (95% CI, 0.42-0.90) in patients with high-risk and low-risk disease, respectively. In the PEACE-1 trial (abiraterone acetate + prednisone), the HRs were 0.75 (95% CI, 0.59-0.95; all de novo) in the overall population and 0.72 (95% CI, 0.55-0.95) and immature in the high-volume and low-volume subgroups, respectively. In the ENZAMET trial (enzalutamide), the HRs were 0.82 (95% CI, 0.63-1.06) in the overall population; 0.73 (95% CI, 0.55-0.99) and 1.10 (95% CI, 0.65-1.86) in the de novo and recurrent subgroups, respectively; and 0.87 (95% CI, 0.66-1.17) and 0.61 (95% CI, 0.33-1.10) in the high-volume and low-volume subgroups. Combination regimens are generally well tolerated, with adverse effects dependent on the profiles of the component drugs.Conclusions and relevanceThe findings of this review show compelling evidence from phase 3 randomized clinical trials in favor of initiating triplet combination therapy for patients with metastatic hormone-sensitive prostate cancer for the best overall survival. Patients who are eligible for chemotherapy should be offered androgen-deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel, particularly patients with high-volume, high-risk, or de novo metastatic disease.

Recommendations on the treatment of metastatic hormone-sensitive prostate cancer: Patient selection

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC.

Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer.

This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.

Role of enzalutamide in primary and recurrent non-metastatic hormone sensitive prostate cancer: a systematic review of prospective clinical trials.

Enzalutamide, a second-generation androgen receptor inhibitor, is indicated for the treatment of metastatic disease, as well as in the treatment of non-metastatic castration resistant prostate cancer (PCa). This systematic review aims to determine outcomes and toxicity in patients with non-metastatic castration sensitive prostate cancer (nmCSPC) treated with enzalutamide in the primary or salvage settings. We performed a systematic review focusing on the role of Enzalutamide in the treatment of nmCSPC, using the PubMed/Medline database. Articles focusing on androgen receptor inhibitors in nmCSPC were included, while articles discussing exclusively metastatic or castration-resistant PCa were excluded. The initial search retrieved 401 articles, of which 15 underwent a thorough assessment for relevance. Ultimately, 12 studies with pertinent outcomes were meticulously examined. Among these, seven studies were dedicated to the investigation of enzalutamide in the primary setting, while the remaining five publications specifically addressed its use in salvage settings. Regardless of the treatment setting, our data revealed two distinct therapeutic strategies. The first advocates for the substitution of enzalutamide for androgen deprivation therapy (ADT), based on the premise of achieving equivalent, if not superior, oncological outcomes while minimizing treatment-related toxicity. The second, adopting a more conventional approach, entails augmenting the effectiveness of ADT by incorporating enzalutamide. Enzalutamide has considerable potential as a therapeutic strategy for nmCSPC, either used alone or in combination with ADT in the primary or in the salvage settings. The use of enzalutamide instead of ADT is an appealing strategy. However, more trials will be required to further understand the efficacy and side-effect profile of enzalutamide monotherapy.

Impact of Circulating Tumor Cell-Expressed Prostate-Specific Membrane Antigen and Prostate-Specific Antigen Transcripts in Different Stages of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer micrometastases. This study evaluated whether a circulating tumor cell (CTC)-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in prostate cancer. We prospectively enrolled 21 healthy individuals and 247 patients with prostate cancer [localized prostate cancer (LPCa), n = 94; metastatic hormone-sensitive prostate cancer (mHSPC), n = 44; and metastatic castration-resistant prostate cancer (mCRPC), n = 109]. The mRNA expression of six transcripts [PSMA, prostate-specific antigen (PSA), AR, AR-V7, EpCAM, and KRT 19] from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. CTC detection rates were 75.5%, 95.3%, and 98.0% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA [hazard ratio (HR), 3.35; P = 0.028) and PSA mRNA (HR, 1.42; P = 0.047] expressions were associated with BCR. Patients with mHSPC with high PSMA (HR, 4.26; P = 0.020) and PSA mRNA (HR, 3.52; P = 0.042) expressions showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expressions were significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. PSMA and PSA mRNA expressions are associated with BCR in LPCa. In advanced prostate cancer, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.

Impact of disease volume on survival efficacy of triplet therapy for metastatic hormone-sensitive prostate cancer: a systematic review, meta-analysis, and network meta-analysis.

Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for metastatic hormone-sensitive prostate cancer (mHSPC). However, the optimal selection of the patient most likely to benefit from triplet therapy remains unclear. We performed a systematic review, meta-analysis, and network meta-analysis to assess the oncologic benefit of triplet therapy in mHSPC patients stratified by disease volume and compare them with doublet treatment regimens. Three databases and meeting abstracts were queried in March 2023 for randomized controlled trials (RCTs) evaluating patients treated with systemic therapy for mHSPC stratified by disease volume. Primary interests of measure were overall survival (OS). We followed the PRISMA guideline and AMSTAR2 checklist. Overall, eight RCTs were included for meta-analyses and network meta-analyses (NMAs). Triplet therapy outperformed docetaxel plus ADT in terms of OS in both patients with high-(pooled HR: 0.73, 95%CI 0.64-0.84) and low-volume mHSPC (pooled HR: 0.71, 95%CI 0.52-0.97). There was no statistically significant difference between patients with low- vs. high-volume in terms of OS benefit from adding ARSI to docetaxel plus ADT (p = 0.9). Analysis of treatment rankings showed that darolutamide plus docetaxel plus ADT (90%) had the highest likelihood of improved OS in patients with high-volume disease, while enzalutamide plus ADT (84%) had the highest in with low-volume disease. Triplet therapy improves OS in mHSPC patients compared to docetaxel-based doublet therapy, irrespective of disease volume. However, based on treatment ranking, triplet therapy should preferably be considered for patients with high-volume mHSPC while those with low-volume are likely to be adequately treated with ARSI + ADT.

Abstract CT232: Intense exercise for survival among men with metastatic prostate cancer: 12-month feasibility results from the INTERVAL-GAP4 trial pilot site at Edith Cowan University, Australia

Abstract Introduction: Men with prostate cancer undertaking moderate-to-vigorous exercise have a marked reduction of 30-60% in all-cause and cancer-related mortality based on observational studies. In 2016, the Intense Exercise for Survival among Men with Metastatic Prostate Cancer (INTERVAL-GAP4) was launched to determine if supervised exercise improves overall survival in men with metastatic prostate cancer. Here, we describe the demographic characteristics, completion rates, exercise adherence, and safety of the first 12 months of the intervention at the pilot site, Edith Cowan University in Perth, Australia. Methods: INTERVAL-GAP4 is a multi-center global randomized controlled phase III trial. Patients are randomly allocated (1:1) to: (intervention) a high intensity combined resistance and aerobic exercise supervised program for 1 year tapering to self-management in year 2; or (control) self-directed unsupervised exercise with print materials. Patients were stratified by site and by disease/treatment status (metastatic hormone-sensitive prostate cancer [mHSPC] or metastatic castration-resistant prostate cancer [mCRPC] and if the latter, treatment modality). The study did not meet recruitment goals and closed to further enrollment in February 2023. Results: 240 participants were evaluated between April 2016-Feb 2023, 60 patients were consented, 52 participants were randomized, and two patients did not receive the allocation, resulting in 50 participants (27 intervention and 23 control). Main reasons for exclusion were not meeting clinical criteria (N=81), time commitment (N=24), unable to contact (N=22), not interested (N=19), and poor physical function (N=13). Median age at randomization was 72 years (IQR: 68, 77), median body mass index (BMI) was 31.7 kg/m2 (IQR: 27.5, 35.7), 94% identified as white, and time since diagnosis was 5 years (IQR: 1, 9). 13 participants (26%) had mHSPC and 37 (74%) had mCRPC. Completion rates were the following at 6 months: 84% completed surveys, 62% exercise testing, and 66% biological samples. Of 42 alive at 12 months: 85% completed surveys, 73% testing, and 73% biological samples. Median exercise adherence was 90% (IQR: 78, 97) for the first 12 months of the study. Adherence was not significantly different for those with mCRPC vs. mHSPC status. There were 10 SAEs in first 12 months; all (100%) were unrelated to the intervention. Conclusions: Exercise training was feasible and safe in men with metastatic prostate cancer with no difference observed in exercise session adherence by disease status. Survey completion was high, while in-person completion rates were affected by the COVID-19 pandemic. Additional analysis of the entire study population (N=145) is ongoing and will be compared with the pilot site. Citation Format: Stacey A. Kenfield, Nicolas H. Hart, Jennette Sison, June M. Chan, Kerry S. Courneya, Fred Saad, Robert U. Newton. Intense exercise for survival among men with metastatic prostate cancer: 12-month feasibility results from the INTERVAL-GAP4 trial pilot site at Edith Cowan University, Australia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT232.

Abstract LB110: Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate cancer

Abstract PurposeProstate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer (PCa) micrometastases. This study evaluated whether a circulating tumor cell (CTCs-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in PCa. Experimental design We prospectively enrolled 21 healthy individuals and 247 patients with PCa (localized PCa [LPCa]: 94; metastatic hormone-sensitive PCa [mHSPC]: 44; and metastatic castration-resistant PCa [mCRPC]: 109). The mRNA expression of six transcripts (PSMA, prostate-specific antigen [PSA], AR, AR-V7, EpCAM, and KRT 19) from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. Results CTC detection rates were 75.5%, 95.3%, and 98% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA (hazard ratio [HR]: 3.35; P=0.028) and PSA mRNA (HR: 1.42; P=0.047) expression was associated with BCR. mHSPC patients with high PSMA (HR: 4.26; P=0.020) and PSA mRNA (HR: 3.52; P=0.042) expression showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expression was significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. Conclusion PSMA and PSA mRNA expression is associated with BCR in LPCa. In advanced PCa, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance. Citation Format: Hyungseok Cho, Seok-Soo Byun, Nak-Hoon Son, Jae Il Chung, Won Ik Seo, Chan Ho Lee, Todd M Morgan, Ki-Ho Han, Jae-Seung Chung. Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB110.

Bone marrow dosimetry in low volume mHSPC patients receiving Lu-177-PSMA therapy using SPECT/CT

BackgroundBone marrow toxicity in advanced prostate cancer patients who receive [177Lu]Lu-PSMA-617 is a well-known concern. In early stage patients; e.g. low volume metastatic hormone sensitive prostate cancer (mHSPC) patients, prevention of late bone marrow toxicity is even more crucial due to longer life expectancy. To date, bone marrow dosimetry is primarily performed using blood sampling. This method is time consuming and does not account for possible active bone marrow uptake. Therefore other methodologies are investigated. We calculated the bone marrow absorbed dose for [177Lu]Lu-PSMA-617 in mHSPC patients using SPECT/CT imaging and compared it to the blood sampling method as reference.MethodsEight mHSPC patients underwent two cycles (3 and 6 GBq) of [177Lu]Lu-PSMA-617 therapy. After each cycle, five time point (1 h, 1 day, 2 days, 3 days, 7 days) SPECT/CT was performed at kidney level. Bone marrow dosimetry was performed using commercial software by drawing ten 1.5 cm diameter spheres in the lowest ten vertebrae to determine the time-integrated activity. Simplified protocols using only 2 imaging time points and 3 vertebrae were also compared. Blood-based dosimetry was based on the blood sampling method according to the EANM guideline.ResultsMean bone marrow absorbed dose was significantly different (p < 0.01) for the imaging based method (25.4 ± 8.7 mGy/GBq) and the blood based method (17.2 ± 3.4 mGy/GBq), with an increasing absorbed dose ratio between both methods over time. Bland Altman analysis of both simplification steps showed that differences in absorbed dose were all within the 95% limits of agreement.ConclusionThis study showed that bone marrow absorbed dose after [177Lu]Lu-PSMA-617 can be determined using an imaging-based method of the lower vertebrae, and simplified using 2 time points (1 and 7 days) and 3 vertebrae. An increasing absorbed dose ratio over time between the imaging-based method and blood-based method suggests that there might be specific bone marrow binding of [177Lu]Lu-PSMA-617.

Recomendaciones de tratamiento en el cáncer de próstata hormonosensible metastásico: selección de pacientes

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC.

Patient-reported Quality of Life and Survival Outcomes in Prostate Cancer: Analysis of the ECOG-ACRIN E3805 Chemohormonal Androgen Ablation Randomized Trial (CHAARTED)

BackgroundChemohormonal therapy with androgen deprivation therapy and docetaxel (ADT + D) improves overall survival (OS) and quality of life (QOL) at 12 mo versus androgen deprivation therapy (ADT) alone in men with metastatic hormone-sensitive prostate cancer (mHSPC). However, the prognostic role of QOL is unknown in this population. ObjectiveTo study the relationship between QOL, disease characteristics, and OS in men with mHSPC. Design, setting, and participantsIn this exploratory post hoc analysis, 790 patients with mHSPC completed the QOL instruments Functional Assessment of Cancer Therapy—Prostate (FACT-P), Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-F), and Brief Pain Inventory (BPI). Outcome measurements and statistical analysisLog-rank test and Cox proportional hazard models tested the association between QOL and OS by clinical and disease characteristics. Results and limitationsBaseline higher FACT-P trended toward improved survival after accounting for clinical variables (hazard ratio [HR] 0.80 [0.62, 1.04], p = 0.09), while higher 3-mo FACT-P was independently associated with better survival (HR 0.76 [0.58, 1.0], p = 0.05). Patients with the poorest QOL (bottom quartile) at baseline and 3 mo had longer survival if they received ADT + D rather than ADT alone (median OS 45.2 vs 34.4 mo, HR 0.75 [0.53, 1.05], p = 0.09, and 48.3 vs 29.3 mo, HR 0.69 [0.48, 0.99], p = 0.05 respectively). In contrast, patients with the best QOL (top quartile) at baseline and 3 mo had comparable survival irrespective of whether or not docetaxel was added (median OS 72.1 vs 51.7 mo, HR 0.92 [0.63, 1.36], p = 0.69, and 69.9 vs 68.9 mo, HR 1.11 [0.73, 1.67], p = 0.63, respectively). Survival was linked with baseline FACIT-F (HR 0.76 [0.57, 1.0], p = 0.05), but not BPI (HR 0.98 [0.75, 1.28], p = 0.90). ConclusionsThree-month QOL had a stronger independent association with survival. The most symptomatic patients had longer survival with the addition of docetaxel; conversely, the least symptomatic patients did not appear to benefit. Consideration of QOL may enhance decision-making and patient selection when choosing chemohormonal treatment in mHSPC. Patient summaryQuality of life independently forecasted the survival of men with metastatic hormone-sensitive prostate cancer in the CHAARTED study. Close tracking of quality of life could help patients and clinicians make decisions about the appropriate treatment in this setting.

#30. Fractures in metastatic hormone-sensitive prostate cancer (mHSPC). Results from two phase 3 trials from the STAMPEDE platform

#30. Fractures in metastatic hormone-sensitive prostate cancer (mHSPC). Results from two phase 3 trials from the STAMPEDE platform

Multidisciplinary Team Approach in Prostate-Specific Membrane Antigen Theranostics for Prostate Cancer: A Narrative Review

In managing prostate cancer, the integration of multidisciplinary team (MDT) with prostate-specific membrane antigen (PSMA) theranostics marks a significant advancement, addressing the disease's spectrum from indolent forms to aggressive metastatic stages. MDTs, comprising urology, oncology, radiation oncology, pathology, radiology, and nuclear medicine experts, are pivotal in delivering tailored, evidence-based care, essential for the varied clinical presentations of prostate cancer. The introduction of PSMA-targeted theranostics and PSMA positron emission tomography imaging has impacted the approach to diagnosis and treatment, offering enhanced precision in disease localization and enabling more nuanced management strategies for conditions such as oligometastatic prostate cancer, metastatic hormone-sensitive prostate cancer, and metastatic castration-resistant prostate cancer. The collaborative approach of MDTs in utilizing PSMA-targeted radioligand therapy emphasizes meticulous patient selection, predictive assessment of therapy response, and careful management of therapy-related toxicities. Additionally, recent strategies, including combination therapies from ENZA-P and Lu-PARP trials, show potential for improving treatment efficacy. This unified approach showcases the critical role of MDTs in optimizing treatment outcomes, underscoring the importance of collaboration in advancing the treatment of prostate cancer with PSMAtargeted therapies, thereby setting a new paradigm in personalized prostate cancer management.

Is there an indication for local treatment in metastasised hormone-sensitive prostate cancer?

In case of newly diagnosed metastasised hormone-sensitive prostate cancer, there are two indications for local treatment: to reduce or avoid local symptoms thus improving quality of life and prolonging survival in a subset of patients. Local treatment must be seen in a multimodal treatment approach and is not a replacement of systemic treatment. In the following review, we highlight the current literature for the different local treatment options, radiotherapy and radical prostatectomy, and try to give indications for which option should be offered to which patient.

Abstract 4988: Responders to combination radiation and PD-1 blockade demonstrate reduced myeloid immunosuppression and enhanced interferon signaling in oligometastatic prostate cancer patients

Abstract Background: Prostate cancer is unresponsive to current immunotherapies such as checkpoint inhibitors. Overcoming this “cold” environment requires rational combination of therapeutic modalities that can prime anti-tumor immunity. Radiation is a potential candidate; however it remains unclear how it should be most productively combined with immunotherapies. Methods: We completed an investigator-initiated clinical trial of newly diagnosed men with oligometastatic, hormone-sensitive prostate cancer (mHSPC, NCT03007732). Patients were randomized to receive anti-PD-1 x 13 cycles (pembrolizumab, Arm 1, n=12), or anti-PD-1 with intraprostatic injections of TLR9 agonist SD-101 (Arm 2, n=11). All patients received SBRT to the prostate tumor during cycle 1, and concomitant hormonal therapy with a GnRH agonist and abiraterone. Response was assessed as PSA &amp;lt; nadir + 2 ng/mL at 15 months after ceasing all cancer therapies. For unbiased correlative immune interrogation of these patients, fresh paired biopsies of primary prostate tumor and PBMCs both before and after radiation and immunotherapy were analyzed by multi-omic single-cell genomics to assess changes with treatment, including T cell repertoire changes. Results: Fourteen of 21 evaluable patients responded by PSA criteria with 3 patients not yet reaching 15 months of post-treatment follow-up. Adverse events included expected IRAEs from anti-PD-1, and flu-like symptoms from SD-101, with no unexpected AEs. Single-cell analysis of tumor biopsies reveals treatment-induced decreases in cytotoxic T cell populations and increases in both immunostimulatory LAMP3+ dendritic cells and immunosuppressive SPP1+ myeloid populations. Treatment increased interferon (IFN) signaling in most myeloid subsets while strongest in LAMP3+ DCs. Compared to non-responders, responders showed less immunosuppression at baseline with depletion of myeloid cells and enhanced IFN activity on LAMP3+ DCs, and treatment-induced IFN activity on cytotoxic T cells. TLR9 agonism also specifically enhanced IFN responses, persistence of cytotoxic T cell clonotypes, and enhanced antigen presentation in tumor cells. Circulating T cells in blood detected shared clones with tissue showing enrichment in cytotoxic phenotype and association with responders. Conclusions: Responders to combination radiation and anti-PD-1 blockade have decreased myeloid immunosuppression and enhanced IFN activity prior to treatment in oligometastatic prostate cancer. This may identify patients likely to respond, and baseline immune setpoints that can be enhanced with improved immunotherapy strategies. Acknowledgements: This work was supported by the Prostate Cancer Foundation and Merck. Merck Sharp &amp; Dohme LLC, Rahway, NJ, USA provided drug and financial support for the study. Citation Format: Zenghua Fan, David Y. Oh, Anthony Wong, Katsuto Shinohara, Hao Nguyen, Caleb Hwang, Hewitt Chang, Alec Starzinski, Tony Li, Christopher De Leon, Marissa Gin, Eliezer Van Allen, Li Zhang, Rahaul R. Aggarwal, Terence W. Friedlander, Eric J. Small, Felix Y. Feng, Lawrence Fong. Responders to combination radiation and PD-1 blockade demonstrate reduced myeloid immunosuppression and enhanced interferon signaling in oligometastatic prostate cancer patients [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 4988.

Abstract 6264: Role of Nuclear ErbB3 localization in regulating ligand-dependent ErbB2-ErbB3 heterodimer activation and downstream targets in prostate cancer

Abstract Objective: Prostate cancer (PCa)-specific nuclear expression of ErbB3, a receptor tyrosine kinase of the epidermal growth factor receptor (EGFR) family, has long been recognized. While an 80kDa nuclear variant of ErbB3 has been identified, full-length 185 kDa ErbB3 also translocates to the nucleus in PCa in a bone microenvironment and androgen status-dependent manner. Here, we studied potential mechanisms by which nuclear ErbB3 may regulate PCa progression. Methods: ErbB3 localization was investigated in vitro (human prostate cancer cell lines, LNCaP, C4-2, 22Rv1) using amiloride or heregulin-1β (ErbB3-specific ligand). ErbB3 expression and subcellular localization were analyzed using immunofluorescent microscopy and subcellular fractionation followed by immunoblot. Physiological readouts included viability, migration and reporter gene assays. Results: Here we show that ErbB3 can occupy a nuclear/perinuclear location in prostate cancer cells. The hormone sensitive PCa line LNCaP expressed higher levels of nuclear ErbB3 compared to castration resistant lines C4-2 and 22Rv1. The diuretic amiloride was previously shown to inhibit ErbB3 internalization by macropinocytosis thus we investigated whether it could also modulate ErbB3 nuclear localization in PCa cells. In LNCaP cells, amiloride dose dependently prevented ErbB3 nuclear transport, whereas in C4-2 and 22Rv1, no such effect was observed. Further analysis revealed that amiloride promoted ErbB3 expression in the membrane, where ErbB3 underwent ligand-dependent phosphorylation, formed ErbB2/ErbB3 dimers, and in turn phosphorylated the downstream targets AKT and ERK1/2 (p42/p44MAPK). On the other hand, EGFR phosphorylation and dimerization were unaffected by amiloride. Our results suggest that ErbB3 is stored in the nuclear region in an inactive form, whereas upon stress induction, including androgen deprivation, ErbB3 is translocated to the plasma membrane, where it is activated by ligand binding, and causes downstream signaling. Conclusion: We previously showed that the EGFR/ErbB2 dual inhibitor lapatinib failed to affect PCa - we now show that this may be due to modulation of nuclear and cytoplasmic ErbB3 expression. Amiloride prevented translocation (and thus expression of) ErbB3 to the nucleus and retained this RTK in the membrane, resulting in the formation of active ErbB2/ErbB3 dimers. Lapatinib was then able to inhibit and inactivate its specific target, ErbB2, thereby inducing significant apoptosis. The above indicates a novel role for nuclear ErbB3 in PCa that can be regulated by the combination of amiloride and lapatinib. Citation Format: Maitreyee K. Jathal, Maria M. Mudryj, Paramita M. Ghosh. Role of Nuclear ErbB3 localization in regulating ligand-dependent ErbB2-ErbB3 heterodimer activation and downstream targets in 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 6264.

Abstract 688: Radium-223 in combination with darolutamide exhibits synergistic antitumor efficacy in LNCaP prostate cancer models

Abstract Radium-223 dichloride (radium-223) is a targeted alpha therapy that binds to newly formed abnormal bone in bone metastases and induces DNA double-strand breaks (DSBs) in cancer cells, osteoblasts and osteoclasts. Radium-223 is used for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Darolutamide is an androgen receptor inhibitor indicated for patients with metastatic hormone-sensitive prostate cancer or non-metastatic CRPC. We studied the antitumor effects of radium-223 in combination with darolutamide using LNCaP human prostate cancer cells in vitro and an intratibial LNCaP model mimicking prostate cancer metastasized to bone. The in vitro antiproliferative effects of radium-223 and darolutamide were determined using LNCaP cells. Gene set enrichment analysis (GSEA) was conducted on RNA sequencing data from LNCaP cells treated with the synthetic androgen R1881 alone or in combination with darolutamide. LNCaP cells were inoculated into the right tibia of male NOD.scid mice. The mice (n=7-9/group) were randomized based on serum prostate-specific antigen (PSA) and treated with vehicle, radium-223 (330 kBq/kg, Q4Wx2, i.v.), darolutamide (100 mg/kg, BID, p.o.), or with a combination of radium-223 and darolutamide, for 41 days. PSA and the bone turnover markers PINP and CTX-I were measured every second week in serum. Tumor-induced abnormal bone area, bone formation rate and radium-223 uptake in tumor-bearing tibiae were determined by X-ray, histomorphometry and gamma counter, respectively. The combination of radium-223 and darolutamide showed synergistic antiproliferative effects with combination indexes between 0.69-0.75 in vitro. GSEA demonstrated a prominent darolutamide-induced downregulation of DNA damage response (DDR) signaling pathways. In vivo, the combination treatment showed synergistic antitumor efficacy (p=0.04) as demonstrated by lower PSA concentrations when compared with the vehicle, radium-223 or darolutamide monotherapies (p=0.004, p=0.011 and p=0.002, respectively). In the vehicle and combination treatment groups, the mean serum PSA was 541% and 95.9% of the pre-treatment level, respectively. Furthermore, radium-223 alone or in combination with darolutamide inhibited increased bone turnover, tumor-induced abnormal bone growth and trabecular bone formation when compared to vehicle. Concurrent administration of darolutamide did not affect radium-223 uptake in tibiae. Radium-223 in combination with darolutamide exhibited synergistic antitumor efficacy both in vitro and in vivo. The synergistic effects could be due to the radiosensitization of cancer cells by darolutamide-induced downregulation of DDR pathways. Our results suggest that the combination of targeted alpha therapy with an androgen receptor inhibitor is a promising treatment strategy for mCRPC. Citation Format: Christoph A. Schatz, Mari I. Suominen, Andreas Schlicker, Matias Knuuttila, Esa Alhoniemi, Sanna-Maria Käkönen, Bernard Haendler, Urs B. Hagemann, Arne Scholz. Radium-223 in combination with darolutamide exhibits synergistic antitumor efficacy in LNCaP prostate cancer models [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 688.

Abstract 3812: Treatment guideline concordance for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the United States in IRONMAN, the International Registry for Men with Advanced Prostate Cancer

Abstract Background: Treatment intensification strategies with an androgen receptor pathway inhibitor (ARPI) and/or docetaxel chemotherapy in addition to androgen deprivation therapy (ADT) are guideline recommended treatment options for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Prevalence of guideline concordant care for mHSPC patients in the US and its changes over time are not well characterized. Methods: The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is a prospective cohort study of patients with newly diagnosed mHSPC and castration-resistant prostate cancer (CRPC). Therapies are captured by site personnel and by directly capturing data from treating physicians via physician questionnaires (PQ). We included all US patients with mHSPC enrolled from 2018 to January 1, 2023 with a completed PQ at enrollment. We examined patient characteristics, first-line treatments for mHSPC, and guideline concordance of first-line treatments. Guideline concordance was defined as a treatment regimen listed in the first National Comprehensive Cancer Network guidelines version for the year prior to treatment. Patients enrolled in clinical trials were excluded from analysis of treatment guideline concordance. Results: Among the 636 US participants with mHSPC, physicians completed PQs for 458 participants (72%). Participants had a median age of 68 years (interquartile range 62 - 75). Three hundred eight (78%) were White, 72 (18%) were Black, 13 (3%) were other races/ethnicities: 65 did not report race. First-line treatment for mHSPC based on the PQ was most commonly ADT + ARPI (59%) followed by ADT + docetaxel (17%), ADT monotherapy (14%), ADT + first-generation antiandrogen (3%), ADT + ARPI + docetaxel (3%), and other treatments (5%). Overall, 384 (86%) participants received first-line treatment that was guideline concordant at the time of treatment. Treatment guideline concordance was highest in 2018 (99%) when ADT monotherapy was considered as guideline concordant but then decreased to 80% in 2019 and remained largely stable from 2019 to 2022 (85%). Overall, rates of guideline concordance were similar when stratified by race (88% for White patients vs 85% for Black patients), age (90% for patients &amp;lt;65 years old vs 85% for patients ≥65 years old), and treatment at a Comprehensive Cancer Center (CCC) (87% at CCC vs 86% at non-CCC). Conclusion: Among patients with mHSPC treated in the US at 38 cancer centers, proportions of guideline concordant first-line treatment were high and remained stable over time, despite changes in approved therapies. Future efforts to understand reasons for treatment decisions will be important to better understand the relatively uncommon situations in which guidelines and actually received treatments differ for patients with mHSPC. Citation Format: Hannah Dzimitrowicz McManus, Lauren Howard, Kerri-Anne Crowell, Terry Hyslop, Jake Vinson, Dana E. Rathkopf, Philip Kantoff, Lorelei A. Mucci, Daniel George, Konrad Stopsack. Treatment guideline concordance for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the United States in IRONMAN, the International Registry for Men with Advanced 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 3812.

Abstract 6875: PIM kinases alter the prostate tumor immune microenvironment

Abstract Prostate cancer is the second leading cause of cancer-related deaths in American men. While prostate cancer patients typically respond to androgen-deprivation therapy, androgen receptor signaling inhibitor (ARSI), and/or taxane chemotherapy, patients inevitably develop resistance, and the disease progresses to an untreatable and lethal form known as castrate resistant prostate cancer (CRPC). Immunotherapy has changed the treatment paradigm for many types of cancer; however, immune checkpoint inhibitors have not shown clinical benefits in CRPC. Clinical and preclinical evidence indicates that this lack of efficacy can largely be attributed to the immunosuppressive tumor microenvironment. Tumor associated macrophages (TAMs) secrete factors that promote tumor progression and suppress antitumor immunity, making them a promising therapeutic target. The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases are serine/threonine kinases that are overexpressed in prostate cancer. PIM regulates many signaling pathways that promote cell proliferation and survival. However, how PIM kinase alters the prostate tumor immune microenvironment and impacts immunotherapy resistance is not well understood. We analyzed primary prostate and metastatic lymph node samples from treatment-naive metastatic hormone-sensitive prostate cancer patients. Prostate cancer samples with PIM1/PIM2/PIM3-high and -low expression were classified by top and bottom quartile, respectively. PIM high tumors had higher expression of immunostimulatory genes (IL1β, TNF, and TNFSF13), increased infiltration of M2 macrophages, B cells, and NK Cells, and a higher T cell inflamed score compared to PIM-low tumors. Our results demonstrate that PIM overexpressing prostate tumors display increased inflammation and infiltration of immunosuppressive immune cells, including M2 macrophages. Due to the changes observed in inflammation, we hypothesized that PIM kinase may regulate macrophage inflammatory signaling. We treated bone marrow derived macrophages with a PIM kinase inhibitor and showed that PIM inhibition suppresses inflammasome signaling and the release of the pro-inflammatory cytokine, IL-1β. Chronic inflammation can lead to the recruitment of TAMs, further promoting resistance to immune checkpoint inhibitors. Utilizing a syngeneic mouse model of prostate cancer, we demonstrated that PIM inhibition in combination with immune checkpoint blockade synergistically decreased tumor growth. Furthermore, immunoprofiling demonstrated that combination treatment enhances T cell activity. Overall, our results suggest that PIM kinase plays an important role in regulating the prostate tumor immune microenvironment and that PIM kinase may be a potential target to enhance the efficacy of immunotherapy for the treatment of prostate cancer. Citation Format: Amber N. Clements, Kai Sutterby, Sachin Kumar Deshmukh, Sharon Wu, Joanne Xiu, Alex Farrell, Milan Radovich, Chadi Nabhan, Elisabeth I. Heath, Rana R. McKay, Alejandro Recio-Boiles, Noel A. Warfel. PIM kinases alter the prostate tumor immune microenvironment [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 6875.