Oligometastatic Hormone-sensitive Prostate Cancer Research Articles

PE054 Cytoreductive radical prostatectomy in hormone-sensitive oligometastatic prostate cancer: Preliminary results on safety and efficacy of a prospective single arm study

PE054 Cytoreductive radical prostatectomy in hormone-sensitive oligometastatic prostate cancer: Preliminary results on safety and efficacy of a prospective single arm study

Epidemiology, treatment patterns, and clinical outcomes in de novo oligometastatic hormone-sensitive prostate cancer.

This study was conducted to better characterize the epidemiology, clinical outcomes, and current treatment patterns of de novo oligometastatic hormone-sensitive prostate cancer (omHSPC) in the United States Veterans Affairs Health Care System. In this observational retrospective cohort study, 400 de novo metastatic hormone-sensitive PC (mHSPC) patients diagnosed from January 2015 to December 2020 (follow-up through December 2021) were randomly selected. omHSPC was defined as five or less total metastases (excluding liver) by conventional imaging. Kaplan-Meier methods estimated overall survival (OS) and castration-resistant prostate cancer (CRPC)-free survival from mHSPC diagnosis date and a log-rank test compared these outcomes by oligometastatic status. Twenty percent (79 of 400) of de novo mHSPC patients were oligometastatic. Most baseline characteristics were similar by oligometastatic status; however, men with non-omHSPC had higher median prostate-specific antigen at diagnosis (151.7) than omHSPC (44.1). First-line (1L) novel hormonal therapy was similar between groups (20%); 1L chemotherapy was lower in omHSPC (5%) versus non-omHSPC (14%). More omHSPC patients received metastasis-directed therapy/prostate radiation therapy (14%) versus non-omHSPC (2%). Median OS and CRPC-free survival (in months) were higher in omHSPC versus non-omHSPC (44.4; 95% confidence interval [CI], 33.9-not estimated vs. 26.2; 95% CI, 20.5-32.5, p=.0089 and 27.6; 95% CI, 22.1-37.2 vs. 15.3; 95% CI, 12.8-17.9, p=.0049), respectively. Approximately 20% of de novo mHSPC were oligometastatic, and OS was significantly longer in omHSPC versus non-omHSPC. Although potentially "curative" therapy use was higher in omHSPC versus non-omHSPC, the percentages were still relatively low. Future studies are warranted given potential for prolonged responses with multimodal therapy inclusive of systemic and local therapies.

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.

A phase 2 single-arm study testing SBRT, adenosine signaling modulation, and immune checkpoint inhibition for men with hormone-sensitive oligometastatic prostate cancer (SBRT-AMICO).

A phase 2 single-arm study testing SBRT, adenosine signaling modulation, and immune checkpoint inhibition for men with hormone-sensitive oligometastatic prostate cancer (SBRT-AMICO).

The metabolic repression effect of carbon-ion radiotherapy in synchronous hormone-sensitive oligometastatic prostate cancer.

Metastatic prostate cancer (PCa) poses a significant public health concern. While radiation therapy (RT) is commonly utilized in the treatment of synchronous oligometastatic hormone sensitive prostate cancer (OM-HSPC), the occurrence of biochemical recurrence still remains. To deepen our understanding and optimize the outcome of OM-HSPC, we conducted this study to investigate the characteristics of PCa progression and explore potential synergistic mechanisms involving carbon-ion radiotherapy (CIRT) and neoadjuvant androgen deprivation treatment (naADT) in OM-HSPC. Metabolomic analysis was conducted with 72 urinary samples (at different timepoints) from 33 Patients (T2-3N0M0-1b) and 18 healthy volunteers by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). MetaboAnalyst website and R software were employed for metabolomic analysis and visualization (using the criteria of p value < 0.05 and |FC|>1.5). The impact of CIRT on metabolism were further verified and explored through in vitro and in vivo experiments. We found that most metabolites (223 out of 233) were upregulated in treatment-naïve PCa samples compared to healthy samples. After naADT, 60 core risk metabolites were still significantly related to PCa's progression, and the glutamine level which was significantly higher in OM-HSPC compared to other groups. Remarkably, after CIRT treatment, the glutamine levels in OM-HSPC were significantly reduced to the level of healthy samples. Experiments further confirmed CIRT's ability to suppress glutamine levels in PCa tumors and its potential enhancement with glutamine deprivation intervention. CIRT with naADT might synergistically inhibit HS-OMPC development, progression and even the ADT resistance through glutamine metabolism repression, moreover, the glutamine metabolism might be a novel target to further improved the efficacy of CIRT.

A Pilot Study of Stereotactic Body Radiotherapy and 177Lu-PSMA-617 for Oligometastatic Hormone Sensitive Prostate Cancer

Stereotactic body radiotherapy (SBRT) is increasingly used for oligorecurrent prostate cancer (OPC). Despite excellent local control, distant metastasis free survival rates are more modest. We hypothesized SBRT outcomes could be optimized with improved staging imaging and integration of a well-tolerated targeted radiopharmaceutical therapy (RLT) for microscopic disease. We report initial results of a prospective, single-institution pilot (NCT05079698) of a novel, PSMA-based theranostic strategy for OPC. Men with castrate sensitive OPC and 1-3 sites of PSMA PET avid disease ("index lesions") and no PSMA non-avid sites were eligible. No androgen deprivation therapy was permitted. Subjects first received 2 cycles of 177Lu-PSMA-617 RLT (7.47±0.14 GBq) spaced 6 weeks apart. In vivo dosimetry was performed during cycle 1. Four weeks post-cycle 2, patients were restaged with 68Ga-PSMA PET for an interim (post-RLT) response assessment. Index lesions were then consolidated with SBRT (9 Gy x 3) irrespective of post-RLT PET response. The primary outcome was feasibility defined as successful completion of protocol-mandated therapy without intercurrent distant failure on post-RLT PET. Six men were treated with nine total index lesions (5 nodal, 3 osseous, 1 visceral). The study met its primary endpoint; all completed required interventions and no distant progression was seen on interim PSMA PET. Treatment was well tolerated; no grade 3+ toxicities, 2/6 had grade 2 toxicities (transient anemia and hyperbilirubinemia) and 5/6 had grade 1 toxicities. Median baseline lesion-level PSMA SUVmax was 16.8±8.7. Median interim SUVmax was 6.2±2.5 and declined for all but one lesion post-RLT (median -65%). Median SUVmax at 3-mos post-SBRT was 3.3±2.5 and decreased for all evaluable lesions (median -80%). Median baseline PSA was 2.01 ng/mL (range: 0.72-4.56) which declined in 5/6 post-RLT. The 6th patient experienced biochemical rise with interim PET showing only greater avidity in the known index lesion and SBRT was completed per protocol. All 4 evaluable patients with at least one post-SBRT follow-up have improved PSA at last visit (range 5.5-12 mos from cycle 1), and 2/4 have undetectable PSA. Composite dosimetry, correlatives and quality of life studies are forthcoming. Our pilot study demonstrates the feasibility of a novel PSMA anchored theranostic strategy combining SBRT with targeted RLT for OPC. Preliminary data suggests promising outcomes, including the possibility of achieving an undetectable biochemical disease state without hormone 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.

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.

A feasibility study of 177Lu-PSMA radioligand therapy alternated with radium-223 in patients with bone-metastatic, oligo-metastatic, hormone-sensitive prostate cancer after curative therapy: The DUET study.

TPS5113 Background: Previous randomized clinical trials have shown an improvement in overall survival in patients with metastatic castration resistant prostate cancer (mCRPC), who have already failed other therapies, treated with 177Lu-PSMA radioligand therapy (RLT). Although 177Lu-PSMA RLT has shown exciting treatment responses in men with mCRPC and suggests a low toxicity profile, it has not been widely investigated in patients with metastatic hormone-sensitive prostate cancer (HSPCa). As of today, treatment with systemic drugs is proof of concept in advanced or metastatic HSPCa, as well as in other cancer types, and leads to improved oncological outcome, potentially by eradicating micro-metastatic disease. As a bone-seeking calcium mimetic, Radium-223 (Ra-223) is incorporated into new bone stroma, predominantly within sclerotic metastatic deposits. The high-energy of the alpha-particle radiation generates double-stranded DNA breaks, offering a potent and highly localized cytotoxic effect in the target areas. In a phase 3, randomized, double-blind, placebo-controlled study, Ra-223 has proven to significantly improve overall survival (by a treatment comprising 1 injection per month, at a dose of 50 kBq per kilogram of body weight intravenously), as compared with placebo. The optimal therapy in patients with oligometastatic bone HSPCa after previous curative treatment has not yet been defined. Methods: This is a single center, interventional, one-arm phase I-II study that prospectively investigates if a treatment strategy in which two types of cytotoxic RLT, i.e., an alpha-emitter and a beta-emitter, alternatively offered to patients with oligometastatic HSPCa, is feasible and safe. Eight patients with low volume, PSMA expressing, radiological progressive HSPCa (minimal 2 bone metastases, maximal 5, and at 0 to 3 lymph node metastases) will be recruited. In these patients, loco-regional radiotherapy or surgery is not an option anymore. The PSA doubling time in participating patients should be less than 6 months. Primary endpoint: To assess the feasibility and safety in patients with bone metastatic, oligometastatic HSPCa, treated by Ra-223 RLT alternated with 177Lu-PSMA RLT Secondary endpoints: Toxicity and (serious) adverse events will be monitored and reported in concordance with the NCI CTCAE v5.0; Assessment of the xerostomia inventory; Prostate-specific antigen (PSA) levels on follow-up at 3, 6 and 12-months; Investigative Treatment: Patients enrolled in the trial will receive three intravenous applications of Radium-223, in a dose of 5.5 kBq/kg body weight at t = 0 weeks, t = 4 weeks and t = 8 weeks (±1), and two intravenous applications of 7.4 GBq 177Lu-PSMA RLT at t = 6 weeks and t = 12 weeks (±1). Clinical trial information: NL81658.029.22.

APPROACH trial: Multimodal approach in patients with mHSPC: A pragmatic, randomized, phase 3 trial of androgen-deprivation therapy (ADT) plus apalutamide (APA) versus ADT plus apalutamide (APA) and local treatment—Meet-URO 29 study.

TPS5115 Background: it is reasonable to offer radiotherapy (RT) to improve outcomes for patients with newly diagnosed M1 prostate cancer with &lt; 5 bone metastases (HORRAD) or low volume disease (STAMPEDE) (Burdett, S et al., Eur. Urol. 2019). Data from clinical randomized trials evaluating feasibility and overall benefit of cytoreductive radical prostatectomy (cRP) in oligometastatic ormone sensitive patients are not available. The rationale for performing cytoreductive radical prostatectomy is to eliminate lethal clones ofcastration-resistant intraprostatic PCa, which can favor the process of metastasis (A Heidenreich et al. Current Opinion in Urology 2020), in order to improve OS and PFS and to prevent local progression and correlated events. Methods: APPROACH is an Italian multicenter study, which is enrolling ~566 pts with oligometastatic hormone sensitive prostate cancer who are candidates to receive treatment with apalutamide. After 6 months from the start of treatment, patients will be randomized 1:1 to receive local treatment or not in addition to apalutamide (investigator's choice between primary radiotherapy and cytoreductive prostatectomy). Primary end point: To determine whether treatment with apalutamide plus ADT for 6 months followed by locoregional treatment with radiotherapy or radical prostatectomy has better efficacy than treatment with apalutamide plus ADT alone in terms of radiographic progression-free survival (rPFS). Secondary end points: To evaluate tumor shrinkage after locoregional approach and to evaluate short and long-term side effects after locoregional surgery or RT, time to PSA progression, time to castration resistance, cancer specific survival, overall survival and quality of life according to EPIC-26 and EQ-5D-5L questionnaires. Clinical trial information: NCT05649943 .

Oligometastatic Hormone-Sensitive Prostate Cancer. Why Radiotherapy?

Androgen deprivation therapy (ADT) has been considered for years the standard initial treatment for patients with metastatic prostate cancer (mPC). Recently published results support the use of taxanes, second-generation antiandrogens or radiotherapy to the primary tumor as part of the treatment in these patients, considering ADT alone as suboptimal. Metastasis-directed therapy (MDT) is used as part of the treatment for oligometastatic patients in different tumor types. In oligometastatic hormone-sensitive prostate cancer the role of MDT is being studied with promising results. In the present review we assess the available evidence for radiotherapy to the primary tumor in newly diagnosed mPC and for MDT in oligometastatic prostate cancer, as well as future directions in this clinical setting.

The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES

BackgroundFew phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment. ObjectiveTo evaluate outcomes for patients with oligometastatic and polymetastatic HSPC treated with enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. Design, setting, and participantsThis was a post hoc analysis of data for 927 patients with nonvisceral metastatic HSPC in the ARCHES trial (NCT02677896). InterventionPatients were randomized 1:1 to enzalutamide (160 mg/d orally) plus ADT or placebo plus ADT with HSPC categorized as oligometastatic (1–5 metastases) or polymetastatic (≥6 metastases). Outcome measurements and statistical analysisThe treatment effect on radiographic progression-free survival (rPFS), overall survival (OS), and secondary efficacy endpoints was evaluated in terms of the number of metastases. Safety was assessed. Cox proportional hazards models were used to generate hazard ratios (HRs). The Brookmeyer and Crowley method was used to generate 95% confidence intervals (CIs) for Kaplan-Meier median values. Results and limitationsEnzalutamide plus ADT improved rPFS (HR 0.27, 95% CI 0.16–0.46; p < 0.001), OS (HR 0.59, 95% CI 0.40–0.87; p < 0.005), and secondary endpoints in patients with oligometastatic or polymetastatic disease (rPFS: HR 0.33, 95% CI 0.23–0.46; p < 0.001; OS: HR 0.55, 95% CI 0.41–0.74; p < 0.001). Safety profiles were generally similar across subgroups. Limitations include the small numbers of patients with fewer than three metastases. ConclusionsThis post hoc analysis demonstrated the utility of enzalutamide, irrespective of metastatic burden or type of oligometastatic disease, and suggests that earlier treatment intensification with systemic potent androgen receptor inhibition is advantageous. Patient summaryThis study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.

Perioperative change of circulating tumor cells in cytoreductive radical prostatectomy for oligometastatic hormone-sensitive prostate cancer: the preliminary safety evidence from long-term oncologic outcomes.

Surgical manipulation has a risk of triggering the shedding of circulating tumor cells (CTCs) in patients with malignancies, However, perioperative change of circulating tumor cells in cytoreductive radical prostatectomy (CRP) for patients with oligometastatic hormone-sensitive prostate cancer (omHSPC) has not yet been well documented. This study aimed to assess whether CRP is a safe procedure for patients with omHSPC by monitoring the perioperative change of CTCs and investigating its impact on long-term oncologic outcomes. We have observed a significant decrease between the median CTC counts before and after surgery (6 vs. 4, p = 0.026). Comparing preoperative and postoperative CTC levels, seven patients increased (CTC increase group), one did not change and nineteen decreased (CTC non-increase group). PSA response rates in CTC increase group were lower than those in CTC non-increase group (73.0% vs 99.8%, p = 0.162), and nadir PSA was higher in CTC increase group (0.043 vs 0.003, p = 0.072). The CTC increase was positively correlated with the nadir PSA (r = 0.386, p = 0.047). The median follow-up period was 71.6months, we found that there was no significant difference in clinical-pathological, operative variables or long-term oncologic outcomes between perioperative CTC increase and non-increase groups. In the entire cohort, the CTC level significantly decreased after surgery. There was no significant differences in long-term oncologic outcomes between the CTC increase and non-increase groups, implying that CRP potentially represents a safe procedure for the treatment of patients with omHSPC. The results need to be confirmed in a prospective large-scale clinical trial.

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.

Prognostic impact of circulating tumor cells in oligometastatic hormone-sensitive prostate cancer following metastasis-directed therapy.

199 Background: Contained within the spectrum of metastatic cancer is an oligometastatic state where metastases are limited in number. Recent prospective data have shown that metastasis directed therapy (MDT) can alter the natural history of oligometastatic disease. In hormone-sensitive prostate cancer (HSPC), the positive clinical effect of MDT has been observed by the phase II STOMP and ORIOLE trials. Circulating tumor cells (CTCs) are a likely origin of the formation of macroscopic metastases. CTCs thus 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 association between presence of CTCs at baseline or day 180 with clinical outcomes in the ORIOLE trial. Methods: ORIOLE was a phase II trial randomizing men with recurrent oligoHSPC with 1-3 metastases to observation (Obs) versus stereotactic ablative radiotherapy (SABR) MDT. Blood samples were prospectively collected at baseline and day 180. Progression-free survival (PFS) was a composite endpoint including any of the following: a PSA rise of at least 2 ng/dL and 25% above nadir; radiologic progression by CT, MRI or bone scan (RECIST v1.1); symptomatic progression of disease; initiation of ADT; or death. Patient blood samples were shipped for analysis on Epic Sciences liquid biopsy platform (Epic Sciences, San Diego, CA). Machine learning algorithms identified CTCs and characterized androgen receptor (AR) expression. Comparisons of patient and tumor characteristics between the groups were performed by two-sample t-tests. Survival curves were generated using the Kaplan-Meier method and p-values were calculated using log-rank test. Analysis was performed using SPSS version 28. Results: A total of 82 samples were collected: 70 from the SABR arm (35 baseline and 35 on day 180) and 12 Obs (7 baseline and 5 on day 180). CTCs were detected in 30/42 samples at baseline (71%, AR+= 7) and in 26/40 samples on day 180 (65%, AR+= 9). In the SABR group there was no difference between CTC+ versus CTC- and AR + versus AR- groups for PSA evaluated at baseline, day 90 or day 180 or Gleason score. With a median follow-up of 41.7 months, PFS was significantly lower in the patients with AR+ versus AR- CTCs at baseline in the SABR arm (p = 0.011, mean PFS: AR+ = 9.3 months, AR- = 27.1 months). The mean biochemical failure-free survival was AR+= 12.9 versus AR-= 29.2 months (p = 0.058). Conclusions: Our preliminary results demonstrate an association between AR+ CTCs at baseline and Day 180 with clinical outcomes following SABR MDT in oligoHSPC. This is the first report examining baseline and dynamic presence of CTCs in oligoHSPC treated from a prospective randomized trial of SABR. Longer follow-up, further analysis and a greater number of patients are needed for a more comprehensive conclusion.

Epidemiology, treatment patterns, and clinical outcomes in de novo oligometastatic hormone-sensitive prostate cancer.

92 Background: Oligometastatic hormone-sensitive prostate cancer (omHSPC) represents an advanced prostate cancer subset where metastasis-directed therapy (MDT) and prostate radiation therapy (RT) may improve clinical response and outcomes; however, there is a lack of published data on the epidemiology, clinical outcomes, and current treatment patterns. As such, we conducted a study to better characterize de novo omHSPC in the United States Veterans Affairs Health Care System (VA). Methods: This observational retrospective cohort study utilized chart abstracted data from the VA electronic medical record, as well as data from the VA Corporate Data Warehouse, a central repository of VA patient medical records. We randomly selected 400 men diagnosed with de novo mHSPC from 1/2015-12/2020. omHSPC was defined as up to 5 bone, lymph node, and/or visceral (excluding liver) metastases in total, identified by conventional imaging (bone scan, CT, and/or MRI). We estimated prevalence, described treatment patterns and used Kaplan-Meier methods to estimate overall survival (OS) and time to castration resistance from date of mHSPC diagnosis. The log rank test was used to compare differences in outcomes between omHSPC and non-omHSPC groups. Results: Of the 400 men with de novo mHSPC, 76 (19%) had omHSPC by conventional imaging. Men with omHSPC and non-omHSPC were similar in age, race, Gleason grade group, comorbidities, and metastatic site (bone and lymph node being most common). Men with non-omHSPC had a higher median PSA at mHSPC diagnosis (147.0) than omHSPC (38.3). The percentage of men on first-line (1L) novel hormonal therapy (NHT) use (most commonly abiraterone or enzalutamide) was similar between groups in the 1L setting (22.4% (omHSPC) vs 20.4% (non-omHSPC)), but the percentage of men on a 1L chemotherapy regimen was lower in omHSPC (5.3%) vs. non-omHSPC (13.6%). Overall, there was a higher percentage of men treated with MDT or prostate RT in omHSPC (13.2%) vs non-omHSPC cases (2.5%). Median OS in months (mos) was higher in men with omHSPC (55.3 mos, 95% CI 35.9-79.0) vs. non-omHSPC (25.9 mos, 95% CI 20.5-31.7, p=0.002). Median time to castration resistance was also longer in omHSPC (not reached [NR], 95% CI 42.2-NR) vs. non-omHSPC (29.3 mos, 95% CI 23.7-36.1, p=0.0014). Conclusions: Our study provides real-world insight into the prevalence, treatment patterns and clinical outcomes for omHSPC using a nationally representative VA sample. Approximately 1 in 5 men with de novo mHSPC were oligometastatic, and OS in men with omHSPC was more than double that of non-omHSPC. Although more men with omHSPC compared to non-omHSPC received potential curative therapy, the percentage was still relatively low. Future studies are warranted as several clinical trials are investigating the potential for prolonged responses with aggressive, multimodal therapy inclusive of systemic and local therapies.

Outcomes with metastasis-directed therapy (MDT) and fixed-duration systemic therapy in oligometastatic hormone-sensitive prostate cancer (omHSPC).

178 Background: Intensification of systemic therapy beyond ADT, with use of novel hormonal agents (NHAs), and radiotherapy (RT) to the prostate have a proven survival benefit in mHSPC. MDT has shown benefit in delaying need for ADT in omHSPC in phase 2 trials. Combination of fixed-duration systemic therapy with MDT (and RT to the prostate in de novo mHSPC) may produce long-term remission and treatment-free survival in selected patients with omHSPC. Methods: Patients with de novo or recurrent omHSPC treated at our institution between 2010-2020 with MDT (+/- prostate RT if de novo) and a fixed duration of systemic therapy completed by September 2022 were identified. There was no limit on number of metastases as long as all sites could be treated with MDT in the view of the treating physician. Oligometastases were defined as bone or soft tissue lesions beyond the pelvic lymph nodes identified on conventional scans (CT, bone scan, MRI) or PET (fluciclovine or PSMA). The primary outcome was freedom from biochemical recurrence (BCR), defined as PSA of &gt;0.02 (if the patient had undergone prior radical prostatectomy) or &gt;2+nadir (if the patient underwent RT) after completion of systemic therapy. Testosterone recovery was defined as serum testosterone &gt;150ng/dL attained after completion of systemic therapy. BCR-free survival after completion of systemic therapy was estimated using the Kaplan Meier method. Results: 32 patients were included. Median age at diagnosis of mHSPC was 67 (range 52-78). 12 patients (38%) had de novo mHSPC while 20 (63%) had oligorecurrent HSPC. Detection of omHSPC was by conventional scans in 23 patients (72%) and by PET only in 9 (28%), and median number of oligometastases was 1 (range 1-6). Median PSA at start of therapy for omHSPC was 8.2ng/mL (range 0.4-1244), with systemic therapy most commonly comprising of ADT and a NHA (abiraterone, enzalutamide, apalutamide, n=26 [82%]); 6 patients (19%) had ADT alone. Median duration of systemic therapy was 24 months (range 6-36), with 3 men (9%) having received prior systemic therapy for mHSPC. MDT consisted of external beam RT (EBRT, n=10, 31%), EBRT + stereotactic body radiotherapy (SBRT, n=8, 25%), or SBRT alone (n=14, 44%). At a median follow-up of 44 months (range 24-127) and 20 months (2-103) after start and completion of systemic therapy respectively, 9 patients (28%) had BCR and 23 (72%) remained free of BCR, of whom 13 (57%) had testosterone recovery. The estimated 2-year BCR-free survival after completion of systemic therapy was 73% (95% CI 51-86). Conclusions: In this carefully selected cohort of men with omHSPC, estimated 2-yr BCR-free survival after completion of therapy was &gt;70% with ~2 years of ADT +/- NHA along with MDT +/- prostate RT (if de novo). Longer follow-up is needed to determine whether this translates to a durable treatment-free remission, and possibly cure, in these patients with omHSPC.

Long-Term Outcomes of Patients on a Phase II Prospective Trial of Oligometastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and External Beam Radiation

<h3>Purpose/Objective(s)</h3> External beam radiation therapy (EBRT) to oligometastases may improve outcomes in patients (pts) with oligometastatic hormone-sensitive prostate cancer (oHSPC) who would traditionally receive androgen deprivation therapy (ADT) alone. To date, follow up (FU) on this cohort has been limited to ∼5 years. We reviewed the long-term outcomes of oHSPC pts treated with EBRT and ADT on an IRB approved prospective clinical trial (NCT00544830). <h3>Materials/Methods</h3> From 2006 to 2011, oHSPC pts with 1-5 metastases (mts) detected by CT and bone scan received 36 weeks of ADT (LHRH agonist + bicalutamide) and consolidative EBRT up to 53 Gy to all visible mts. When indicated, the primary tumor or prostate bed was treated with EBRT up to 78 Gy or 66 Gy, respectively. Primary objectives were long-term progression free survival (PFS), overall survival (OS) and local control of treated mts. <h3>Results</h3> 29 pts (median age 66.9, range 49.5-79.3) were treated on this protocol. Median number of mts per patient was 1 (range 1-5) and EBRT was administered to 51 lesions (37 bone, 10 pelvic lymph nodes [LNs], 4 non-pelvic LNs) to a median biologically equivalent dose of 53 Gy (range 47-66). Median Gleason score was 8 (range 5-10) and median baseline PSA was 11.4 (range 1.0-74.5). 15 pts had de novo mts, and 14 pts had oligorecurrent mts. 22 pts (75.9%) had bone mts. 25 pts (86%) reached PSA nadir of <0.2 within 9 months of completing ADT. Median FU was 9.9 years (yrs, range 0.2-14.4) for all pts. Median OS was 9.7 yrs (95% Confidence Interval [CI]:5.8-Not Reached [NR]) and 48.3% (95%CI: 29.5-64.8) at 10 years. Of the 10 pts (34%) still alive at last FU, two remain progression-free. Median PFS for all pts was 1.9 yrs (95%CI: 1.6-2.2) and 12.4% (95%CI: 3.4-27.6) at 10 years. Pts who presented with de novo mts had significantly improved (p=0.04) median PFS (2.0 yrs, 95%CI: 1.3-6.0) compared to oligorecurrent pts (1.8 yrs, 95%CI: 1.0-2.0). Pts who presented with LN only mts had improved (p=0.13) median PFS (5.8 yrs, 95%CI: 1.2-NR) compared to pts with bony mts (1.8 yrs, 95%CI: 1.3-2.0). For pts still alive after 5 years, median number of lines of treatment was 6 (range 0-15). At the time of FU, 16 pts (55%) had local control of all EBRT treated mts. Across all pts, 70.6% (n=36) of all treated mts were controlled. The mts that locally progressed had previously been controlled for median 3.4 yrs (range 1.7-10.5), comprising 11 bony mts, 2 pelvic LNs, and 2 non-pelvic LNs. <h3>Conclusion</h3> Our results compare favorably with other reported studies of oHSPC and provide new insights into their long-term outcomes. Metastasis-directed EBRT in this population of oHSPC pts resulted in longer than expected OS. The ongoing study adding radium-223 in addition to ADT and SBRT (NCT03361735) will seek to further delay recurrence in oHSPC with bone mts.

Second generation anti-androgens and androgen deprivation therapy with radiation therapy in the definitive management of high-risk prostate cancer.

Evolving data suggest that men with high-risk localized prostate cancer may benefit from more potent androgen receptor inhibition in the context of curative intent radiotherapy. Recently updated American Society for Clinical Oncology (ASCO) evidence-based guidelines and the National Comprehensive Cancer Network (NCCN) Guidelines have updated recommendations for the consideration of adding second generation anti-androgens to androgen deprivation therapy (ADT) in men receiving radiation therapy (RT) for noncastrate locally advanced high and very high risk nonmetastatic or node positive prostate cancer. We conducted a comprehensive review of existing published and abstract presented evidence behind RT with ADT for the definitive management of high-risk prostate cancer, particularly focused on the current phase II and III trial evidence for the addition of second generation anti-androgens to ADT in definitive RT treatment of high-risk prostate cancer and specifically focused on the recent STAMPEDE trial results with abiraterone acetate. We review the biological mechanisms in which second generation anti-androgens may help mitigate ADT resistance and provide radiosensitization through inhibition of DNA repair. Finally, we discuss ongoing clinical trials of potent androgen receptor (AR) inhibitors with ADT in this non-metastatic high-risk radiotherapy setting that may inform on future treatment guidelines. Recent data suggest an overall survival benefit as well as increased probabilities of disease free and metastasis free survival in men with high and very high-risk localized, node positive, and oligometastatic hormone sensitive prostate cancer with abiraterone acetate and prednisone and support the use of potent AR inhibitors in this setting after informed decision making.