Oligometastatic Prostate Cancer Research Articles

Defining oligometastatic state in uro-oncological cancers.

Oligometastatic tumors illustrate a distinct state between localized and systematic disease and might harbor unique biologic features. Moreover, these tumors represent a different clinical entity, with a potential of long-term disease control or even cure, therefore they receive growing attention in the field of urologic oncology. Currently, there is no consensus on the definition of oligometastatic prostate cancer, most experts limit it to a maximum of three to five lesions and involvement of no more than two organs, excluding visceral metastases. Quality data on oligometastatic bladder cancer is scarce, however, a consensus of experts defined it as a maximum of three metastatic lesions, either resectable or suitable for stereotactic therapy, without restrictions to the number of organs involved. As for kidney cancer, a maximum number of five metastases, without limitations to the location are defined as oligometastatic, with an important implication of timing of developing metastases since diagnosis of the primary tumor. Defining oligometastatic state among urological tumors reflecting their distinct biological and clinical behavior is crucial to establish a sound framework for future clinical trials, and to facilitate guideline and policy formulation for improved patient care. Advancements in molecular imaging are expected to transform the field of oligometastatic urologic tumors in the future.

Disrupting prostate cancer research: Challenge accepted; report from the 2023 Coffey-Holden Prostate Cancer Academy Meeting.

The 2023 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, themed "Disrupting Prostate Cancer Research: Challenge Accepted," was convened at the University of California, Los Angeles, Luskin Conference Center, in Los Angeles, CA, from June 22 to 25, 2023. The 2023 marked the 10th Annual CHPCA Meeting, a discussion-oriented scientific think-tank conference convened annually by the Prostate Cancer Foundation, which centers on innovative and emerging research topics deemed pivotal for advancing critical unmet needs in prostate cancer research and clinical care. The 2023 CHPCA Meeting was attended by 81 academic investigators and included 40 talks across 8 sessions. The central topic areas covered at the meeting included: targeting transcription factor neo-enhancesomes in cancer, AR as a pro-differentiation and oncogenic transcription factor, why few are cured with androgen deprivation therapy and how to change dogma to cure metastatic prostate cancer without castration, reducing prostate cancer morbidity and mortality with genetics, opportunities for radiation to enhance therapeutic benefit in oligometastatic prostate cancer, novel immunotherapeutic approaches, and the new era of artificial intelligence-driven precision medicine. This article provides an overview of the scientific presentations delivered at the 2023 CHPCA Meeting, such that this knowledge can help in facilitating the advancement of prostate cancer research worldwide.

Prostatectomy in oligometastatic prostate cancer: a call for high-quality evidence.

The systematic review by Saouli et al. investigates the role of radical prostatectomy (RP) in managing oligometastatic prostate cancer (omPCa) [1]. They analyzed the existing literature to assess the oncological and functional outcomes of RP for these patients. RP is feasible and has an acceptable risk of complications. However, the lack of consensus on the definitions of omPCa and the low-quality evidence of the available comparative and retrospective studies, RP in omPCa should not be recommended outside of clinical trials.

A commentary on "assessment of treatment outcomes: cytoreductive surgery compared to radiotherapy in oligometastatic prostate cancer - an in-depth quantitative evaluation and retrospective cohort analysis".

A commentary on "assessment of treatment outcomes: cytoreductive surgery compared to radiotherapy in oligometastatic prostate cancer - an in-depth quantitative evaluation and retrospective cohort analysis".

PCO24-175: Immune Cell Dynamics After Radiotherapy for Oligometastatic Prostate Cancer.

PCO24-175: Immune Cell Dynamics After Radiotherapy for Oligometastatic Prostate Cancer.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer

PurposeEmerging data suggest metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease and has been proposed as a biomarker for treatment response. Herein we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and materialsWe performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation therapy who underwent PSMA-PET/CT prior to and after (median 6.2 months, range 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT SUVmax was measured for all lesions and PSMA response was defined as percent change in SUVmax of the least responsive lesion. PSMA response was evaluated as both a continuous variable and dichotomized as PSMA responders with a complete/partial response (at least 30% reduction in SUVmax) and PSMA non-responders with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated conventional imaging defined metastasis-free survival (MFS) with Kaplan-Meier and cox regression. ResultsA total of 131 patients with 261 treated metastases were included in the analysis, with median follow-up of 29 months (IQR 18.5-41.3). Following SABR, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated PSMA response as a continuous variable was associated with significantly worse MFS (HR=1.003, 95%CI 1.001-1.006; p=0.016). Patients classified as PSMA responders were found to have significantly improved median MFS of 39.9 vs 12 months (p=0.001) compared to PSMA non-responders. Our study is limited as it is a retrospective review of a heterogenous population. ConclusionsFollowing SABR, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

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.

The Evaluation of Clinical and Intravoxel Incoherent Motion Parameters of Primary Lesion in Oligometastatic Prostate Cancer.

In the realm of cancer studies,the differences among the biological behavior of oligometastatic prostate cancer (OPCa), localized prostate cancer (LPCa), and widely prostate cancer (WPCa) are still unclear. The purpose of our study was to assess the clinical and intravoxel incoherent motion (IVIM) parameters of tumor burden in OPCa. In addition, the correlation between clinical and IVIM parameters and the prostate-specific antigen nadir (PSAN) and time to nadir (TTN) during initial androgen deprivation therapy (ADT) in OPCa was explored. It was found that the IVIM parameters could effectively differentiate LPCa and WPCa, as well as LPCa and OPC. Moreover, Gleason score (GS) was positively correlated with PSAN, while prostate volume was positively correlated with TTN. About 54 patients were included in this retrospective study (mean age=74±7.4 years). ADC, D, D*, and f were acquired according to the biexponential Diffusion Weighted Imaging (DWI) model. The Kruskal-Wallis test was used to test the differences in clinical and IVIM parameters among the three groups. The Receiver Operating Characteristic (ROC) curve was used to evaluate the discrimination abilities. The Area Under the Curve (AUC) was compared using the DeLong test. Furthermore, Spearman correlation analysis was performed to assess the correlation between clinical and IVIM parameters of PSAN and TTN during initial ADT with OPCa. There were significant differences among the three groups observed for age, PSA, GS, ADC, D and D* values (P&#60;0.05). Multi-parameter pairwise comparison results showed that significant differences between LPCa and WPCa were observed for the age, PSA, GS, ADC, D and D* values (P<0.05). However, D* was different between the LPCa and OPCa groups (P=0.032). GS showed a significant positive correlation with PSAN (Rho=0.594, P=0.042), and prostate volume showed a significant positive correlation with TTN (Rho=0.777, P=0.003). The IVIM parameters can effectively differentiate LPCa and WPCa, as well as LPCa and OPCa. Moreover, there was a certain trend in their distribution, which could reflect the tumor burden of PCa.

Abstract 4995: Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic prostate cancer

Abstract Metastasis-ablative radiotherapy is a new therapeutic approach that prolongs survival in patients with advanced cancers. Tumour irradiation can elicit an immunogenic cell death resulting in the expansion of tumour-reactive T cells and eradication of both irradiated and distant non-irradiated metastases, referred to as the “abscopal effect”. This abscopal response, nevertheless, is observed in a minority of patients suggesting uncharacterized mechanisms that prevent robust systemic anti-tumor immune response. Tumour-derived extracellular vesicles (TdEVs) have recently emerged as mediators of antitumor immunity but their immunomodulatory role in response to radiotherapy remains largely unknown. Recent clinical studies by our lab have demonstrated that circulating levels of tumour-derived extracellular vesicles (tdEVs) are elevated in response to radiotherapy and high tdEV concentrations are associated with reduced levels of peripheral cytotoxic CD8+ T cells and higher risk of disease recurrence in advanced prostate cancer. Based on our findings, we hypothesize that radiotherapy induces the release of tumor-derived EVs that suppress anti-tumor immunity. Prostate cancer cells (PC3 and DU145) were irradiated with clinically used doses of ionizing radiation (20Gy x 1 or 10Gy x 3 fractions) and tdEVs were co-cultured with human CD8+ T cells to measure their proliferation and cytotoxic activity. Increased levels of tdEVs were released by tumour cells treated with radiotherapy. A higher frequency of impaired T cell cytotoxic activity and a reduction in CD8 T cell proliferation was found in the 10Gy x 3 radiation regimen. Proteomic analysis and western blot showed an increased expression of the immune checkpoint molecule B7-H3 on the tumour cell surface and tdEVs in response to radiotherapy. While coculture of CD8 T cells with B7-H3 depleted tdEVs led to recovery of T-cell cytotoxic ability, overexpression of the B7-H3 in tdEVs inhibited cytotoxic activity. This study provides a rationale for future studies in which we will test the immune-mediated effects of radiotherapy-induced tdEVs in immunocompetent mouse models and investigate B7-H3 blockade as a therapeutic approach to boost abscopal response in the treatment of advanced prostate cancer. Citation Format: Chisom J. Uzendu, Yohan Kim, Roxane R. Lavoie, Haidong Dong, Sean Park, Fabrice Lucien-Matteoni. Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic 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 4995.

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.

Assessment of treatment outcomes: cytoreductive surgery compared to radiotherapy in oligometastatic prostate cancer - an in-depth quantitative evaluation and retrospective cohort analysis.

The management of oligometastatic prostate cancer, defined by its few metastatic sites, poses distinct clinical dilemmas. Debates persist regarding the most effective treatment approach, with both cytoreductive surgery and radiotherapy being key contenders. The purpose of this research is to thoroughly evaluate and compare the effectiveness of these two treatments in managing patients with oligometastatic prostate cancer. A comprehensive search of the literature was carried out to find pertinent publications that compared the results of radiation and cytoreductive surgery for oligometastatic prostate cancer.A meta-analysis was conducted in order to evaluate both the short- and long-term survival.Furthermore, utilizing institutional patient data, a retrospective cohort research was conducted to offer practical insights into the relative performances of the two treatment regimens. Five relevant studies' worth of data were included for this meta-analysis, which included 1425 patients with oligometastatic prostate cancer.The outcomes showed that, in comparison to radiation, cytoreductive surgery was linked to a substantially better Cancer Specific Survival (CSS) (hazard ratio [HR]: 0.70, 95% [CI]: 0.59-0.81, P<0.001) and Overall Survival (OS)(HR, 0.80; 95% [CI], 0.77-0.82; P < 0.01).The two therapy groups' Progression Free Survival (PFS) and Castration Resistant Prostate Cancer Free Survival(CRPCFS), however, did not differ significantly (HR: 0.56, 95% CI: 0.17-1.06; HR: 0.67, 95% CI: 0.26-1.02, respectively). Out of the 102 patients who were recruited in the retrospective cohort research, 36 had Cytoreductive Surgery(CRP), 36 had radiation therapy (primary lesion), and 30 had radiation therapy (metastatic lesion). The follow-up time was 46.3 months (18.6-60.0) on average. The enhanced OS in the CRP group (OS Interquartile Range (IQR): 45-60 months) in comparison to the radiation group (OS IQR: 39.0-59.0 months and 25.8-55.0 months respectively) was further supported by the cohort research. Furthermore, CRP had a better OS than both radiation (primary region) and radiotherapy (metastatic region), with the latter two therapeutic methods having similar OS. This meta-analysis and retrospective research provide valuable insights into the comparative efficacy of cytoreductive surgery and radiotherapy for oligometastatic prostate cancer. While short term survival(PFS,CRPCFS) were similar between the two groups, cytoreductive surgery exhibited superior CSS and OS.Adverse event rates were manageable in both modalities.These findings contribute to informed treatment decision-making for clinicians managing oligometastatic prostate cancer patients. Further prospective studies and randomized controlled trials are essential to corroborate these results and guide personalized therapeutic approaches for this distinct subset of patients.

Metastases-directed radiotherapy in castration resistant oligo metastatic prostate cancer: A multicentric retrospective study from the French group COLib

Oligometastases aredefined as a number of detectable metastases less or equal to 5. In castrate-resistant oligo metastatic prostate Cancer (CR oligoM PC), Metastases-Directed Ablative radiotherapy (MDRT) is poorly investigated. Our study retrospectively reviewed the cases of CR oligoM PC treated with MDRT in 8 French high-volume radiotherapy centers.OS and PFS are defined as the delay between the first day of MDRT and death (OS) or progression according to PCWG criteria (PFS). OS and PFS are evaluated according to Kaplan Meyer, curves are compared with log rank test. Logistic regression was used to identify predictive factors for outcome: bone versus node metastasis, ISUP grade, PSA doubling Time (PSADT) at the time of MDRT, time to castration resistance.107 patients were included in the study, among those 197 metastases received MDRT. For the overall population, the median follow-up was 25.2 months (1,4–145). OS was 93 % at 2 years and 81,4% at 3 years. At 2 years, 100 % of patients with node-only metastasis were alive versus 88,7% among those who have bone metastases (p = 0,72). The median PFS was 12,6 months (IC 95 % [9,6; 17]), with no difference among patients with node only disease versus the rest of the cohort.The PFS was 18,2 months (10,0; 32,4) in patients with PSADT >6 months versus 10,7 months (8,9; 14,3) when PSADT was inferior to 6 months. However, this difference did not reach significant.We did not find a correlation neither between ISUP grade (1–2 versus 3–4-5) and PFS, nor between hormone-sensitivity duration and PFS.Patients receiving MDRT for CR oligoM PC have a good prognosis with 81,6% OS at 3 years. PSA DT longer than 6 months could be related to better PFS. MDRT strategy could postpone the onset of new systemic treatment with median PFS >1 year.

Radical prostatectomy versus radiotherapy as local therapy for primary tumors in patients with oligometastatic prostate cancer.

We compared radical prostatectomy (RP) and radiotherapy (RT) as local therapies for primary tumors and examined their associations with survival outcomes and urinary tract complications in patients with oligometastatic prostate cancer (omPC). We evaluated the data of 85 patients diagnosed with omPC who underwent local therapy for primary tumors between January 2008 and December 2018. Of the 85 patients, 31 underwent prostate RT, while 54 underwent RP. Oligometastatic disease was defined as the presence of fewer than five metastatic lesions without visceral metastasis. Urinary tract complications, progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) were evaluated using the Kaplan-Meier method and Cox regression analyses. Patients treated with RT showed higher prostate-specific antigen levels. There was no significant difference in the 5-year PFS (52.5% vs. 37.9%, p=0.351), CSS (67.6% vs. 84.7%, p=0.473), or OS (63.6% vs. 73.8%, p=0.897) between the RT and RP groups. In the multivariate analyses, the type of local therapy was not associated with PFS (hazard ratio [HR]=1.334, p=0.356), CSS (HR=0.744, p=0.475), or OS (HR=0.953, p=0.897). Therefore, RP seems to be a possible treatment option for patients with omPC, exhibiting oncologic outcomes comparable to those with RT.

Efficacy and safety of combination neoadjuvant chemo-hormonal therapy and robot-assisted radical prostatectomy for oligometastatic prostate cancer.

Efficacy and safety of combination neoadjuvant chemo-hormonal therapy and robot-assisted radical prostatectomy for oligometastatic prostate cancer.

[Metastasis-directed therapy in prostate cancer].

Metastasis-directed therapy (MDT) in oligometastatic prostate cancer (omHSPC) is playing an increasingly important role in therapy with the aim of delaying disease progression, the start of systemic treatment or switching systemic treatment to improve the patient's overall prognosis. Molecular imaging as prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging allows metastases to be detected with ahigher sensitivity and specificity. This means that they can be detected early and made accessible for treatment. The standard therapy for oligo-mHSPC is androgen deprivation (ADT), which is supplemented by novel hormonal therapeutics (NHT). Afew small prospective trials have shown an extension of the ADT-free interval and progression-free survival (PFS), particularly in metachronous oligo-mHSPC, by MDT, usually radiotherapy. Additional ADT can further extend the PFS in particular. There are hardly any prospective data for synchronous oligo-mHSPC. Despite the currently still poor evidence, MDT is playing an increasingly important role. The still unclear definition of oligometastasis and the large number of influencing factors make it difficult to compare current data. Large multicenter prospective data are still pending. It is also important to clarify the effect of limited ADT in combination with NHT in the treatment of synchronous and metachronous oligo-mHSPC with MDT. In synchronous oligo-mHSPC in particular, further benefit of additional local therapy of the primary in combination with MDT should also be investigated.

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.

[Local therapies for oligometastatic hormone-sensitive prostate cancer].

Oligometastatic, hormone-sensitive prostate cancer (omHSPC) is increasingly diagnosed due to the implementation of molecular imaging. OmHSPC is mostly defined as amaximum of four bone metastases without visceral metastases on conventional imaging. This study highlights the existing evidence regarding local treatment of omHSPC, taking into account molecular imaging and modern therapies. Narrative review article based on expert consensus and national/international guideline recommendations, supported by anonsystematic literature search in PubMed (MEDLINE). The authors consider the cited studies as the most significant works in this regard and these were selected to illustrate developments and fundamental concepts, without claiming completeness. Initially, the STAMPEDE study prospectively demonstrated an oncologic benefit of radiotherapy (RT) to the prostate in addition to androgen deprivation therapy for omHSPC. At 3years, overall survival (OS) was 81% with RT versus 73% without RT (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.52-0.90; p = 0.007). However, this benefit was not observed in polymetastatic HSPC (HR 1.07; 95% CI 0.90-1.28; p = 0.4). In astudy by Dai etal., local therapy for omHSPC was performed surgically in 85% of cases, also demonstrating an OS advantage (HR 0.44; 95% CI 0.24-0.81; p = 0.008). OmHSPC should be treated using adjunctive RT. Preliminary prospective evidence shows comparable efficacy with prostatectomy. Modern systemic combination therapies challenge the role of local therapy.

Systemic and tumor-directed therapy for oligometastatic prostate cancer (SOLAR): A phase II trial for veterans with de novo oligometastatic prostate cancer.

163 Background: Treatment paradigms for oligometastatic castration-sensitive prostate cancer patients are evolving. Molecular imaging improves staging, intensified systemic and primary tumor directed therapy improves survival, metastasis-directed therapy improves local control. The impact of combining these imaging and therapeutic approaches into a planned multimodal treatment strategy is unknown. Here we report a prospective phase II single-arm trial combining local, metastasis-directed, and intensified systemic therapies of limited duration with the objective to durably render Veterans free of progression off therapy. Methods: Veterans with de novo M1a/b prostate cancer and 1-5 radiographically visible M1 lesions underwent radical local treatment, intensified systemic therapy for six months (leuprolide, abiraterone acetate with prednisone, apalutamide), and metastasis-directed stereotactic ablative radiotherapy (SBRT). Radical local therapy was either radical prostatectomy (n=12) with lymph node dissection and post-operative radiotherapy (pT≥3a, N1, or positive margins) or radical radiotherapy (n=12) directed to the prostate, SVs, and pelvic LNs. The primary endpoint was the percentage of patients achieving an undetectable serum PSA (for radical prostatectomy) or &lt;2 ng/mL (for radical radiotherapy) six months after recovery of testosterone to ≥150 ng/dL. Secondary endpoints included time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability. Results: Twenty-eight patients enrolled and 4 dropped out (3 prior to start of treatment). All were staged by PSMA PET/CT except two (one by Fluciclovine PET/CT, and one by NaF PET/CT, CT, MRI). Twenty-nine percent were M1a, seventy-one percent were M1b. Median follow-up was 30 months (range 20 - 61 months). Mean and median number of M1 metastases were both two. Sixty-two percent completed all planned systemic therapy without dose modification. One did not recover testosterone after 29 months. Twenty-two had &gt;6 months follow-up after testosterone recovery, 19 of 22 (86%) remain free of any progression (primary endpoint). Three had metastatic progression, one poly nodal M1a progression, one multiple bone metastases, one multiple bone and nodal metastases. Grade 2 and 3 toxicities for primary tumor therapy were 46% and 4%; SBRT 0% and 0%; systemic therapy 42% and 4%. There was one Grade 4 toxicity. Conclusions: Although a small trial, a majority of patients with molecular imaging defined de novo oligometastatic prostate cancer treated with primary and metastasis-directed therapy with intensified systemic therapy of limited duration remained free of progression with a recovered testosterone off all active therapy. Clinical trial information: NCT03298087 .

Prognostic value of PSMA-extracellular vesicles in oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy: A multi-center observational study.

191 Background: Two randomized clinical trials have demonstrated that SABR can prolong time to progression in oligometastatic castration-sensitive prostate cancer (omCSPC) patients. However, there is a need for predictive tools to identify patients who will benefit from SABR alone or with systemic therapy. We investigated the prognostic value of PSMA-positive extracellular vesicles (PSMA+EVs) in a blinded observational study using blood samples from three independent patient cohorts. Methods: We obtained plasma samples from 157 omCSPC patients treated with SABR from the ORIOLE cohort (N=30, JHU) and STOMP-like cohorts (N=80, UGhent; N=47, Iridium Net). Baseline PSMA+EV levels (EV/ml) were measured by nanoscale flow cytometry. Primary clinical endpoints were biochemical progression (bPFS) and radiographic progression (rPFS). Optimal cutoffs for PSA (ng/ml) and PSMA+EV (EVs/ml) were defined as the point with the most significant log-rank test split. Kaplan-Meier curves and univariate Cox regression models were used to determine the association of PSMA+EV levels with clinical outcomes. Results: Twenty percent of patients (N=157 total) were diagnosed with bone scan, 79% with PET imaging, and 1% with other modalities. Ninety-four percent of patients presented with ≤3 metastases on imaging. In the pooled STOMP-like cohorts, median bPFS was 27.9 and 18.0 months for PSMA+EV low and high groups, respectively (p=0.039). Median rPFS was 36.0 versus 27.0 months (p=0.029). In the ORIOLE cohort, median bPFS was 24.3 and 5.9 months in PSMA+EV low and high, respectively (p=0.021). Median rPFS was 36.0 versus 11.1 months (p=0.019). High baseline PSMA+EV levels were associated with higher risk of both biochemical and radiographic progression (Table). Combination of baseline PSA low and PSMA+EV low outperformed either biomarker alone and better predicted risk of disease progression after SABR. Conclusions: While prospective biomarker-guided trials are warranted, a PSMA+EV blood test can aid patient selection by identifying omCSPC patients who may have durable responses to SABR without ADT. [Table: see text]

Dissecting tumor-immune dynamics and radiotherapy response in oligometastatic prostate cancer.

213 Background: Radiation therapy (RT) can improve survival in oligometastatic prostate cancer (OMPC) patients (pts). Reports implicate immune system contribution to both local tumor control and systemic regression of metastases. Understanding molecular and immune drivers of clinical responses in irradiated OMPC pts may elucidate mechanisms of RT-driven antitumor immune activity. Methods: Prospective samples from consented pts with OMPC (de novo/oligorecurrent) receiving RT included baseline (pre-RT) and 3 post-RT blood samples (RT end, 3-, 6-months). Peripheral blood mononuclear cells (PMBC) were obtained at each timepoint. PBMC sample barcoding and antibody labeling was performed prior to analysis by mass cytometry by time of flight (CyTOF). Data were debarcoded/analyzed using standard deconvolution/gating/clustering algorithms. Wilcoxon signed-rank tests identified longitudinal differences in comparison to baseline. P &lt;0.05 denotes significance. Results: Between 2020-2022, 14 OMPC pts (56 samples) met inclusion criteria (2 de novo, 12 oligorecurrent). All received androgen deprivation therapy. De novo OMPC pts received simultaneous RT to the prostate, pelvis, and OM lesions. 6/12 oligorecurrent pts received simultaneous RT to a pelvic field along with OM lesions, while the remainder received RT to the OM lesions alone. Median follow-up was 17 months (r, 3-29). Four pts (28.6%) experienced recurrence (defined by PSA progression). Median time to recurrence after RT was 10.5 months. Significant differences in immune cell subsets after RT compared to pre-RT levels were identified by CyTOF analysis. CD4+ naïve cells peaked 6 months post-RT, while CD4+ effector memory (EM) cells peaked immediately post-RT (p=0.0012) and decreased to baseline levels at 3 months. CD4+ effector cells expressing TIGIT, OX40, ICOS, and CD69 were significantly more abundant immediately post-RT (p&lt;0.05) compared to baseline. CD8+ cells expressing ICOS increased post-RT and were significantly increased at 6 months (p=0.03). In marked contrast to recurrent pts, non-recurrent pts exhibited increasing CD4+ T regulatory cells that peaked 6 months post-RT (p=0.04) and CD4+ EM cells that peaked post-RT (p=0.02). CD4+ effector cells expressing ICOS (p=0.01) and PD-1 (p=0.01) were both increased immediately post-RT, while cells expressing 4-1BB continued to increase and peaked 6 months post-RT (p=0.04). These changes were not observed or not significant in the recurrent population. Conclusions: Longitudinal immune cell subset changes can be observed after RT for OMPC. These data support immune activation, particularly immediately post-RT in non-recurrent pts, with some longitudinal changes lasting up to 6 months. Further analyses include TCR sequencing, inclusion of serum proteomics, and baseline genomic markers that may predict immune system activation and clinical outcomes.