Oligometastatic Prostate Cancer Patients Research Articles

Machine learning predicts conventional imaging metastasis-free survival (MFS) for oligometastatic castration-sensitive prostate cancer (omCSPC) using prostate-specific membrane antigen (PSMA) PET radiomics

PurposeThis study investigated imaging biomarkers derived from PSMA-PET acquired pre- and post-metastasis-directed therapy (MDT) to predict 2-year metastasis-free survival (MFS), which provides valuable early response assessment to improve patient outcomes. Materials/MethodsAn international cohort of 117 oligometastatic castration-sensitive prostate cancer (omCSPC) patients, comprising 34 from John Hopkins Hospital (JHH) and 83 from Baskent University (BU), were treated with stereotactic ablative radiation therapy (SABR) MDT with both pre- and post-MDT PSMA-PET/CT scans acquired. PET radiomic features were analyzed from a CT-PET fusion defined gross tumor volume ((GTV) or zone 1), and a 5 mm expansion ring area outside the GTV (zone 2). A total of 1748 PET radiomic features were extracted from these zones. The six most significant features selected using the Chi2 method, along with five clinical parameters (age, Gleason score, number of total lesions, untreated lesions, and pre-MDT prostate-specific antigen (PSA)) were extracted as inputs to the models. Various machine learning models, including Random Forest, Decision Tree, Support Vector Machine, and Naïve Bayesian, were employed for 2-year MFS prediction and tested using leave-one-out and cross-institution validation. ResultsSix radiomic features, including Total Energy, Entropy, and Standard Deviation from pre-PSMA-PET zone 1, Total Energy and Contrast from post-PSMA-PET zone 1, and Entropy from pre-PSMA-PET zone 2, along with five clinical parameters were selected for predicting 2-year MFS. In a leave-one-out test with all the patients, random forest achieved an accuracy of 80 % and an AUC of 0.82 in predicting 2-year MFS. In cross-institution validation, the model correctly predicted 2-year MFS events with an accuracy of 75 % and an AUC of 0.77 for patients from JHH, and an accuracy of 78 % and an AUC of 0.80 for BU patients, respectively. ConclusionOur study demonstrated the promise of using pre- and post-MDT PSMA-PET-based imaging biomarkers for MFS prediction for omCSPC patients.

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.

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.

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]

P128 - The influence of the prostate radiotherapy dose in the prediction of complete response in synchronous oligometastatic prostate cancer patients

P128 - The influence of the prostate radiotherapy dose in the prediction of complete response in synchronous oligometastatic prostate cancer patients

1797P Application of novel machine learning model in [68Ga] Ga-PSMA-11 PET/CT: Predicting survival in oligometastatic prostate cancer patients

1797P Application of novel machine learning model in [68Ga] Ga-PSMA-11 PET/CT: Predicting survival in oligometastatic prostate cancer patients

Impact of Prophylactic Pelvic Lymph Node Irradiation in De-Novo Oligometastatic Prostate Cancer.

To evaluate the impact of prophylactic pelvic nodal irradiation in de-novo oligometastatic prostate cancer treated with radiotherapy (RT) for both primary tumor and all metastatic lesions. This was a single-center prospective cohort study. De novo oligometastatic prostate cancer patients with RT for both primary tumor and all metastatic lesions were included. Kaplan-Meier method, log rank test and cox regression were used to calculate OS and PFS. PFS included PSA failure, local or distant failure assessed by imaging. This study analyzed 202 patients from 10/2011 to 1/2022 with median follow-up of 48 months. A total of 126 (62.4%) patients were treated with pelvic lymph node RT. The dose was 47.5 Gy with 1.9 Gy per fraction. Among them, 66 (32.7%) patients were treated with whole pelvic RT (WPRT), which the upper limit was at the aortic bifurcation. 60 (29.7%) patients were treated with mini-WPRT, which the upper limit was at the lower margin of obturator foramen. The incidence of diarrhea (P = 0.038) and leukocyte reduction (P = 0.040) in the WPRT subgroup during radiotherapy was significantly higher than that in the mini-WPRT and non-pelvic RT subgroup. For the whole cohort, the median OS and PFS were not reached. The subgroup analysis showed that the elective pelvic nodal irradiation could improve PFS (P = 0.042). However, there was no difference of PFS between standard WPRT and mini-WPRT. The study suggests that for de-novo oligometastatic prostate cancer, elective pelvic nodal irradiation may improve PFS. For patients who cannot tolerate WPRT, mini-WPRT may be an alternative option. However, it needs to be verified in the prospective RCT study.

PSMA-Positive Extracellular Vesicles Predict Disease Recurrence in Oligometastatic Castration-Sensitive Prostate Cancer Treated with Stereotactic Ablative Radiotherapy: Analysis of the ORIOLE trial

Stereotactic ablative radiation therapy (SABR) can prolong progression free survival in oligometastatic prostate cancer (omPC) patients. However, predictive tools to identify those who will benefit from SABR are necessary. Our group was the first to demonstrate that plasma levels of prostate cancer-derived extracellular vesicles (ProstEVs) correlate with tumor burden and predict disease progression in omPC after SABR. Herein, we conducted a blinded validation study using plasma samples from the ORIOLE randomized phase 2 clinical trial in castration-sensitive patients. Plasma samples from 46 omPC patients from the Baltimore ORIOLE trial: a 2:1 ratio randomization to SABR vs observation (NCT02680587). Baseline PSMA+ ProstEV levels were measured by standardized and calibrated nanoscale flow cytometry using fluorescent PSMA antibodies. Median ProstEV levels was used as cut-off for low and high levels. Kaplan-Meier curves and Cox regression models were used to determine the association of ProstEV levels with clinical outcomes [PSA progression-free survival (psaPFS) and radiographic distant progression free survival (rPFS)]. No association was observed between number of metastatic lesions or baseline PSA and plasma ProstEV levels. The rPFS for patients treated with SABR was 29.6 months. The rPFS for patients treated with SABR with high and low ProstEV levels were 11.1 months and 36 months, respectively (Hazard Ratio: 2.85; 95% CI, 1.01-7.48; P = 0.02). The psaPFS for patients treated with SABR was 11.9 months. The psaPFS for patients with high and low ProstEV levels were 5.9 months and 24.3 months, respectively (HR: 2.44; 95% CI, 1.00-5.94; P = 0.03). ProstEVs is the first blood biomarker of tumor burden that can prognosticate the risk of disease recurrence in omPC patients treated with SABR. While biomarker-guided trials are warranted, our validation study strengthens the clinical value of ProstEVs for personalized radiation therapy.

Prospective Characterization of Circulating Tumor Cells in Hormone Sensitive Oligometastatic Prostate Cancer Patients on a Metastasis-Directed Therapy Trial

Prospective data have shown that metastasis-directed therapy (MDT) can alter the natural history of oligometastatic disease. In hormone-sensitive prostate cancer (HSPC), the clinical effect of MDT has been validated by STOMP, ORIOLE and SABR-COMET phase II trials. Circulating tumor cells (CTCs) are likely the source for the formation of macroscopic metastases. CTCs may provide an approach for identifying subgroups of patients with oligometastatic HSPC (oligoHSPC) that would benefit most from MDT. Our main goal was to evaluate the feasibility of CTC detection and subtypes in oligoHSPC patients that may benefit from MDT. ORIOLE randomized men with recurrent HSPC with 1-3 metastases to observation (Obs) vs. stereotactic ablative radiotherapy (SABR) MDT. Blood samples were prospectively collected at baseline (D0) and 6-mos (D180) and shipped for analysis on Epic Sciences liquid biopsy platform (Epic Sciences, San Diego, CA). Machine learning algorithms identified CTCs and characterized androgen receptor (AR) and PSMA expression. Association with clinical factors and outcomes were examined. Biochemical failure-free survival (BFFS) event was a PSA rise of at least 2 ng/mL and 25% above nadir. Progression-free survival (PFS) was a composite endpoint including BFFS event, radiologic progression (RECIST v1.1); symptomatic progression; initiation of ADT; or death. Comparisons of patient and tumor characteristics performed by two-sample t-tests. Survival curves were generated by the Kaplan-Meier method and evaluated by the log-rank test. Effect of SABR on post-SABR on CTC levels were calculated by McNemar test. A total of 82 samples were collected in ORIOLE: 70 SABR (35 D0 and 35 D180) and 12 Obs (7 D0 and 5 D180). 30/42 men had CTCs detected on D0 (71%; AR+ = 7, PSMA+ = 13) and in 26/40 on D180 (65%; AR+ = 9, PSMA+ = 8). Median follow-up was 41.7-mos. There was no association between CTC presence or subtypes (AR+ or PSMA+) with Gleason score or PSA. PFS was significantly lower in the patients with AR+ vs. AR- CTCs on D0 in the SABR arm (p = 0.011, median PFS: AR+ = 9.3- vs. AR+ = 27.1-mos). The median BFFS trended towards a difference for AR+ = 12.9- vs. AR- = 29.2-mos (D180, p = 0.058). SABR had no effect on the presence or subtypes of CTC at D180. Baseline and dynamic CTC levels and their subtypes in oligoHSPC from the ORIOLE randomized trial of MDT was examined. AR+ CTCs at baseline and 6-mos were correlated with clinical outcomes following SABR. Longer follow-up, further analysis and a greater number of patients are needed for a more comprehensive conclusion.

Oligometastatic Prostate Cancer Treated with Stereotactic Body Radiation Therapy: The Role of Three-Dimensional Tumour Volume in Patient Survival

AimsThe definition of oligometastatic prostate cancer (OPCa) is currently based solely on the maximum number of detectable metastases, as there are no validated biomarkers available. The aim of this study was to identify novel predictive factors for OPCa patients who underwent metastases-directed therapy. Materials and methodsThis monocentre, retrospective study included consecutive OPCa patients with a maximum of five metastases in up to two organs, detected with choline- or PSMA-positron emission tomography, who were treated with metastases-directed stereotactic body radiation therapy. Endpoints were overall survival and progression-free survival, assessed with Kaplan–Meier analysis. Univariate and multivariable Cox regression was carried out to evaluate the association between clinical factors and survival outcomes. ResultsBetween 2009 and 2021, 163 patients and 320 metastases were treated with 226 stereotactic body radiation therapy courses. The median three-dimensional metastatic tumour volume was 4.1 cm3, with a range from 0.01 to 233.4 cm3. In total, 87 (53.4%), 21 (12.9%) and 55 (33.7%) metastases were classified as cN1, cM1a and cM1b, respectively. The median follow-up was 28.5 months. The rates of overall survival at 1, 3 and 5 years were 89.5% (95% confidence interval 83.4–93.4), 74.9% (95% confidence interval 66.1–81.7) and 57.2% (95% confidence interval 45.8–67.1), respectively. Multivariable analysis showed that overall survival reduced with the increase in three-dimensional total tumour volume (hazard ratio 1.93, 95% confidence interval 1.06–3.52; P = 0.030) and confirmed a significant difference between cN1 versus cM1a-b disease (hazard ratio 1.81, 95% confidence interval 1.01–3.25; P = 0.046). The cut-off value of total volume correlated with the highest risk of death was 20 cm3 (hazard ratio 2.37, 95% confidence interval 1.34–4.18; P = 0.003). The median progression-free survival was 17.8 months, with 1-, 3- and 5-year rates of 63.7% (95% confidence interval 55.4–70.9), 31.5% (95% confidence interval 22.8–40.6) and 24.7% (95% confidence interval 16.0–34.3). ConclusionsThis study identified three-dimensional total tumour volume and the site of oligometastases as significant predictors of survival in OPCa patients treated with metastases-directed therapy. These parameters can potentially be used to personalised treatment and improve patient outcome.

Systemic therapy escalation after stereotactic body radiation therapy for oligometastatic hormone-sensitive prostate cancer

PurposeTo evaluate the oncological outcome after stereotactic body radiation therapy (SBRT) for oligometastatic hormone-sensitive prostate cancer (omHSPC) patients. Materials-MethodsIn this retrospective, observational, multi-institutional study, omHSPC patients (≤5 metastases) underwent SBRT. Primary endpoint was systemic therapy escalation-free survival (STE-FS) after SBRT. Local (LR), distant (DR), prostatic (PR) and isolated biochemical (iBR) relapses were reported with progression-free survival (PFS) and overall survival (OS). Prognostic factors for STE-FS were investigated. Toxicity was reported. ResultsFrom 01/07 to 09/19, 119 pts with omHSPC underwent SBRT. With a MFU of 34 months [12–97], median STE-FS was 33.4 months (95%CI 26.6–––40.1). Median OS was not reached and PFS was 22.7 months (CI95% 18.6–––32.3). Post-SBRT-PSA remained stable or decreased in 87 pts (73.1%). Progression events (LR, MR, PR, iBR) were observed in 72 pts (60.5%), among whom 6 relapsed in the irradiated area (local control rate: 95%). DR, BR, PR were observed in 44 pts (37%), 21pts (17.7%) and 2 pts (1.7%) respectively. In multivariate analysis, post-SBRT biochemical response was an independent prognostic factor for STE-FS. Grade ≥ 3 toxicity occurred in 1pt. ConclusionWith excellent local control and tolerance, SBRT for omHSPC patients represents an attractive approach to defer systemic therapeutic escalation and prevent its side effects. Accurate patient selection for SBRT requires more data with longer follow-up and higher numbers of patients pending the results of upcoming randomized trials.

Real-world evidence of outcomes of oligometastatic hormone-sensitive prostate cancer patients treated with metastasis-directed therapy.

To investigate characteristics and outcomes of oligometastatic hormone-sensitive prostate cancer (mHSPC) patients undergoing metastases-directed therapy (MDT) with external beam radiation therapy (EBRT). We relied on an institutional tertiary-care database to identify mHSPC patients who underwent EBRT as MDT between 12/2019 and 12/2022. Main outcomes consisted of progression to metastatic castration-resistant prostate cancer (mCRPC) and overall mortality (OM). Oligometastatic was defined as ≤3 metastases and bone and/or lymph node deposits were treated with conventional doses up to 54 Gy or with hypofractionated stereotactic regimes of median 24 Gy (20-27 Gy). Overall, 37 patients treated with EBRT as MDT were identified. The median follow-up was 13 months. Median age at MDT was 71 years and 84% exhibited ECOG performance status 0. The median baseline PSA at diagnosis was 10 ng/mL. Overall, primary local therapy consisted of radical prostatectomy (65%), followed by external beam radiation therapy to the prostate (11%), focal therapy (8%), and palliative transurethral resection of the prostate (5%). Overall, 32% exhibited de novo oligometastatic mHSPC. Bone metastases were present in 78% versus 19% lymph node metastases versus 3% both. The distribution of targeted oligo-metastases was 62% versus 38% for respectively one metastasis versus more than one metastasis. Androgen deprivation therapy (ADT) was combined with MDT in 84%. Moreover, 19% received combination therapy with apalutamide/enzalutamide and 12% with abiraterone or docetaxel. The median time to mCRPC was 50 months. In incidence analyses, 13% developed mCRPC after 24 months. OM after 24 months was 15% in mHSPC patients receiving MDT. Significant OM differences were observed after stratification into targeted metastatic burden (<0.05). No high-grade adverse events were recorded during MDT. Our real-world data suggest that MDT represents a safe treatment option for well-selected oligometastatic mHSPC patients.

PO-1504 Quality of life in oligometastatic prostate cancer patients treated with SBRT using EORTC form

PO-1504 Quality of life in oligometastatic prostate cancer patients treated with SBRT using EORTC form

Randomized phase II trial in prostate cancer with hormone-sensitive OligometaSTatic relapse: Combining stereotactic ablative radiotherapy and durvalumab (POSTCARD GETUG P13): Study protocol

BackgroundAs in other solid tumors, increasing evidence indicates that patients diagnosed with a limited number of prostate cancer metastases, so-called oligometastases, have a better prognosis than patients with extensive metastatic disease. Stereotactic body radiotherapy (SBRT) is now considered an option in this population.Programmed death-1 (PD-1) and its ligands (PD-L1) are targeted by immune checkpoint inhibitors. Preclinical studies have shown that the tumor immune microenvironment changes when combining radiotherapy with immunotherapy, especially with hypofractionated radiotherapy.The oligometastatic setting appears to be the most relevant clinical situation for evaluating the immune response generated by radiotherapy and immune checkpoint inhibitors in patients with an intact immune system.We hypothesize that durvalumab will enhance the immune response following SBRT targeting oligometastatic lesions. Our purpose is to demonstrate, via a randomized 2:1 phase II trial, that SBRT (3 fractions) with durvalumab in oligometastatic hormone-sensitive prostate cancer patients would improve progression-free survival in patients with prostate cancer with up to 5 metastases compared to patients who exclusively received SBRT. MethodsThis is a multicentric randomized phase II study in French academic hospitals. Patients with prostate cancer and up to 5 metastases (lymph node and/or bone) were randomized into a 2:1 ratio between Arm A (experimental group), corresponding to durvalumab and SBRT to the metastases, and Arm B (control group), corresponding to SBRT alone to the metastases. The study aims to accrue a total of 96 patients within 3 years. The primary endpoint is two-year progression-free survival and secondary endpoints include androgen deprivation therapy-free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response. DiscussionThe expected benefit for the patients in the experimental arm is longer life expectancy with acceptable toxicity. We also expect our study to provide data for better understanding the synergy between immunotherapy and radiotherapy in oligometastatic prostate cancer.

Difficulties in Defining Oligometastatic Prostate Cancer: Implications for Clinical Trial Accrual and Community Practice Adoption of Metastasis-Directed Therapy Approaches

Metastasis-directed therapy is widely utilized for oligometastatic prostate cancer patients, but standard imaging does not always identify metastases definitively and, even with PSMA PET, there may be equivocal findings. Not all clinicians have access to detailed imaging review, particularly outside of academic cancer centers, and PET scan access is also limited. We sought to understand how imaging interpretation impacted recruitment to a clinical trial for oligometastatic prostate cancer. IRB approval was obtained to review medical records from all patients screened for the institutional IRB-approved clinical trial for men with oligometastatic prostate cancer involving androgen deprivation plus stereotactic radiation to all metastatic sites, as well as radium223 (NCT03361735). Clinical trial inclusion required at least one bone metastatic lesion and no more than five total sites of metastasis, including soft tissue sites. Tumor board discussion records were reviewed, along with results from additional radiology studies ordered or confirmatory biopsies performed. Clinical characteristics such as PSA level and Gleason score were studied for association with likelihood of oligometastatic disease confirmation. At the time of data analysis, 18 subjects were deemed eligible and 20 were not eligible. The most common reasons for ineligibility were no confirmed bone metastasis in 16 patients (59%) and too many metastatic sites in 3 (11%). The median PSA of eligible subjects was 3.28 (range 0.4-45.5), whereas the median PSA of those found to be ineligible was 10.45 (range 3.7-26.3) when there were too many metastases identified, and 2.7 (range 0.2-34.5) when metastases were unconfirmed. PET imaging (PSMA or fluciclovine PET) increased the number of metastases, while MRI resulted in downstaging to non-metastatic disease. This research suggests that additional imaging (i.e., at least two independent imaging modalities of a possible metastatic lesion) or tumor board adjudication of imaging findings may be critical to correctly identify patients appropriate for enrollment in oligometastatic protocols. This should be considered as trials of metastasis-directed therapy for oligometastatic prostate cancer accrue and results are translated to broader oncology practice.

Savremeni pristup u lečenju oligometastatskog karcinoma prostate

Oligometastatic disease is defined as an intermediate state between localized and widespread metastatic disease. Oligometastatic prostate cancer is generally defined by the presence of five or fewer metastatic sites on imaging. In the era of precision and personalized cancer care, the introduction of more sensitive imaging technologies and the availability of safe and effective localized non-or minimally invasive treatment options, have led to an increase in the incidence and clinical interest in oligometastatic prostate cancer. In addition, the therapeutic paradigm for oligometastatic prostate cancer is evolving toward a more aggressive approach. Retrospective studies have shown that in the metastatic setting, treatments such as radical prostatectomy and local or metastasis-directed radiation therapy can be performed with minimal risk of toxicity and may enhance clinical outcomes. As there is insufficient data to draw reliable conclusions about their impact on survival, aggressive approaches in the treatment of oligometastatic prostate cancer should be considered only in the context of prospective clinical trials, with the patient informed of the limited evidence of benefit. The current inconsistent approach of detecting and treating oligometastatic prostate cancer patients will need to be standardized in order for future clinical studies to be properly performed and, more importantly, compared. These crucial conditions will reveal if oligometastasis diagnosis and therapy should be included in the standard clinical practice of prostate cancer patients.

Radiotherapy of the Primary Tumor and All Metastatic Lesions in Oligometastatic Prostate Cancer

<h3>Purpose/Objective(s)</h3> The aim of this study was to evaluate the survival in oligometastatic prostate cancer patients treated with radiotherapy (RT) for both primary tumor and all metastatic lesions. <h3>Materials/Methods</h3> This was a single-center cohort study. Oligometastatic prostate cancer patients with RT for both primary tumor and all metastatic lesions were included. Kaplan–Meier method, log rank test and cox regression were used to calculate OS and PFS. PFS included PSA failure, local or distant failure assessed by imaging. <h3>Results</h3> This study analyzed 395 patients from 10/2011 to 1/2022 with median follow-up of 42 months. 264 patients (66.8%) were hormone sensitive (HSPC) and 131patients (33.2%) were castrate resistant (CRPC) at the time of RT. 212 patients (53.7%) were synchronous oligometastatic status, 58 patients (14.7%) were metachronous oligometastatic status, and 105 patients (26.6%) were oligoprogressive status. PSMA-PETCT was used for 238 men (60.3%). Before radiotherapy, 12 patients (3.0%) did not receive androgen deprivation therapy (ADT), 252 patients (63.8%) were treated with luteinizing hormone releasing hormone analogue (LHRHa) with or without bikaluamide. 131 patients (33.2%) were treated with LHRHa combined with novel ADT (abiraterone, enzalutamide, apalutamide, etc.), including 3 patients treated with enzalutamide, 2 patients treated with apalutamine, and the rest treated with abiraterone. The most common fractionation scheme of the primary tumor was 2.8Gy for 25 fractions (81.5%). The median BED₃ was 135.3Gy (IQR:128.3-135.3Gy). A total of 247 (62.5%) patients were treated with whole pelvic RT (WPRT). A total of 718 metastatic lesions were treated with RT. The median BED₃ was 121.3Gy (IQR:113.3-131.3Gy). For the whole cohort, the PFS and OS were 62.5% and 92.7% at 3 year, 53.1% and 81.7% at 5 years. Median PFS for men with HSPC was not reached compared with 10 months in men with CRPC. On univariable analysis, HSPC, shorter interval between diagnosis and RT, lower pre-RT PSA, lower Gleason score, lower metastatic burden/volume, use of WPRT, ADT type, chemotherapy were associated with improved PFS. <h3>Conclusion</h3> Our study suggests that RT for the primary tumor and all metastatic lesions has better survival than clinical studies of prostate radiotherapy alone, especially for patients with HSPC, shorter interval between diagnosis and RT and lower metastatic burden/volume.

Stereotactic ablative radiotherapy for oligometastatic prostate cancer.

The present study assessed clinical outcomes of stereotactic body radiotherapy (SBRT) in oligometastatic prostate cancer patients. Between 2017 and 2020, 37 lesions (12 osseous and 25 nodal targets) detected with conventional and/or functional imaging, were treated in 29 patients (pts), in different clinical settings: de novo oligometastatic (2 pts), oligorecurrent castration-sensitive (19 pts), castration-resistant (6 pts) prostate cancers and oligoprogressive disease during systemic therapy (2 pts). SBRT was delivered with volumetric modulated arc therapy up to a total dose of 21 Gy given in 3 fractions for bone and 30 Gy in 5 fractions for nodal metastases. A total of 34% of pts received hormonal therapy. We evaluated biochemical control [prostate serum antigen (PSA) increase < 10%)], progression free-survival (PFS) (time from SBRT to biochemical progression), local control (LC) (time from SBRT to in-field radiologic progression), hormone/systemic therapy-free survival, acute and late toxicities. At 3 months, biochemical response was observed in 20/29 pts (69%). At a median follow-up of 17 months (range 6-33), 8/20 (40%) of the 3-month responders remained free from progression. Two-year PFS and LC were 37% and 70%, respectively. In-field progression occurred in 3/37 (8%) lesions. Hormone/systemic therapy was delayed by an average of 11.6 months (range 3-28). No significant difference in PFS based on the type of lesion or concomitant endocrine therapy was observed and no toxicity > grade 2 was reported. SBRT for oligometastatic prostate cancer offers a good biochemical/local control and tangible delay of hormone/systemic therapy without major toxicities.

Systemic Therapy Postponement after Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer

<h3>Purpose/Objective(s)</h3> To evaluate the oncological outcome after stereotactic body radiation therapy (SBRT) for oligometastatic (OM) prostate cancer (PC) patients. <h3>Materials/Methods</h3> In this retrospective observational multi-institutional study (Health-data-hub N°F20210402112942), patients with OM (≤ 5) PC underwent SBRT. While patients were enrolled irrespective of PC initial treatment, castration sensitive (CS)/resistant (CR) and synchronous (SM)/metachronous (MM) metastatic disease status were taken into account. Primary endpoint was systemic therapy postponement (STP) after SBRT. Oncological outcome was assessed by post-SBRT biochemical response, local (LR; in SBRT field), metastatic (MR), prostatic (PR) and isolated biochemical (iBR) relapses. PSA kinetic (PSAdt; velocity) and prognostic factors for STP were investigated. Toxicity was reported (CTCAE v5). <h3>Results</h3> From 01/07 to 09/19, 169 pts (median age 71.4 y [48.7 – 100.1]) underwent SBRT. At the time of SBRT, 151 pts (89.3%) and 18 pts (10.7%) were MM and SM respectively and 119 pts (70.4%) and 50 pts (29.6%) were CS and CR respectively. Median PSA, PSAdt and velocity were 2.4 ng/ml [0.01 – 277], 5.2 months [0.9 – 45.2] and 2.3 ng/ml/an [0.1 – 25.9] respectively. Median time between initial PC/metastatic disease (TPCMD) and metastatic disease/SBRT were 68.9 months [1.9 – 273.4] and 3.1 months [0.1 – 97.9]. Metastatic anatomic sites were pelvic (PLN) and extra-pelvic lymph nodes (EPLN), bone and brain for 58 pts (34.4%), 15 pts (8.9%), 92 pts (54.4%) and 4 pts (2.4%) respectively. SBRT regimens were 27 Gy/3f (29%), 35 Gy/5f (24.3%), 36 Gy/6f (18.3%) and other (28.4%). With a MFU of 27.5 months [1 – 100.5], median time between SBRT/1^st PSA control was 2 months [0.5 – 29]. PSA decreased in 67.4%, was stable in 9.4% and increased in 23.2%. Eighty-eight pts (52.1%) underwent post-SBRT systemic therapy after a median STP of 15.4 months [2.6 – 86.9]. One hundred and thirty events (LR, MR, PR, iBR) were observed in 106 pts (62.7%), among whom 13 (12.3%) relapsed in the irradiated area (local control rate: 92.3%). MR, PR, iBR were observed in 82 pts (77.4%), 33 pts (31.1 %) and 2 pts (1.9 %) respectively. Prognostic factors for STP after SBRT were: hormonal status (CS vs CR: 20.9 vs 10.8 months; p < 0.001), post-SBRT biochemical response ([declined + stable] PSA vs increased PSA: 21 vs 11 months; p = 0.004) and TPCMD (< 42 vs ≥ 42 months; p < 0.001). G≥3 toxicity occurred in 4 pts: 2 pts with G3 post-SBRT fracture (1 surgery), 1 pt with G3 radiation pneumonitis and 1 pt with G4 intracranial hypertension (emergency surgery). <h3>Conclusion</h3> SBRT for oligometastatic prostate cancer is an option to postpone systemic therapy, mainly for CS and MM patients with an acceptable toxicity profile. Patient selection criteria remain a crucial goal in order to refine SBRT indications, while the impact of combination with systemic therapy remains under investigation.