Median bPFS Research Articles

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]

Total and anatomically contextualized quantitative 18F-DCFPyL PET at biochemical recurrence to predict subsequent biochemical progression-free survival in patients with prostate cancer.

33 Background: PSMA PET has been shown to detect more metastasis and alter management at biochemical recurrence (BCR), but it remains to be determined that it changes oncologic outcome. We assessed the quantitative parameters on 18F-DCFPyL PET at BCR and evaluated their association with tumor volume, metastatic locations with the subsequent biochemical progression free survival (bPFS). Methods: This is a retrospective image analysis and longitudinal follow up of a prospective study evaluating 18F-DCFPyL PET in BCR. Patients were treated with androgen deprivation therapy (ADT) and/or metastatic directed therapy (MDT) based on imaging findings. The 18F-DCFPyL PET images were quantitatively analyzed by the aPROMISE application, a semi-automated software for comprehensive analysis and structured reporting of PSMA PET/CT. aPROMISE uses deep learning to segment detailed anatomical information from the CT images and uses this information in combination with the PET image to detect and quantify candidates for prostate cancer lesions. The reader works in tandem with the software to vet the final list of lesions, from which the quantitative assessments and final report is created automatically. Based on the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. SUV mean, PSMA positive total tumor volume (PSMAttv) and aPSMA scores, a quantitative score for tumor burden measuring the interaction of tumor volume and uptake stratified by local tumors (aPSMA-miT), regional lymph nodes (aPSMA-miN) and distant metastases (aPSMA-miMa for extrapelvic metastases, miMb for bone metastases and miMc for other organ metastases) were obtained based on the miTNM classification. The association of these quantitative parameters with the subsequent bPFS was evaluated. Results: 143 patients (age 70.5 ± 7.9, range 50 -93 years; median PSA 2.8, range 0.12 – 1125.9 ng/mL) were included in the quantitative image analysis. 80 of 143 patients (56%) had nodal metastases 51/143 patients (36%) had bone metastases, only 16 of 143 patients (11%) had visceral metastases. With median follow up of 40 months, 82 of 143 patients (57%) have progressed again biochemically after MDT. The median bPFS was 26.9 months. Quantitative analysis of 18F-DCFPyL PET found that the subsequent bPFS is significantly associated with aPSMA-miMb ( P = 0.003), aPSMA-miN ( P = 0.005), aPSMA-miT ( P < 0.001), and PSMAttv ( P = 0.006), but not with SUVmean, SUVmax or aPSMA-miMc. Conclusions: Quantitative image analysis of 18F-DCFPyL PET at BCR may be useful in predicting the subsequent bPFS. Given many patients were treated with MDT and/or ADT, clinical implication of the findings remains to be elucidated to guide treatment intensification based on findings on 18F-DCFPyL PET.

Oligometastatic Prostate Cancer in the Modern Era: Post-SBRT Chronicle

<h3>Purpose/Objective(s)</h3> Recent randomized phase II trials have demonstrated the clinical benefit of incorporating modern functional radionuclide imaging modalities and stereotactic body radiotherapy (SBRT) in the management of oligometastatic prostate cancers. An improved understanding of the clinical course following metastasis-directed therapy can assist in the role and timing of systemic treatment as a part of complex management decisions. Here, we provide long-term follow-up data for oligometastatic castration-sensitive (CSPC) and resistant (CRPC) prostate cancer following SBRT. <h3>Materials/Methods</h3> We retrospectively evaluated patients with oligometastatic prostate cancer (≤3 lesions) identified on 11C-Choline PET who were treated with SBRT. Outcomes reported were biochemical progression-free (BPFS), local (LPFS), distant (DPFS), and overall (OS) survival. Survival curves were generated by Kaplan-Meier analysis and compared by Cox proportional hazards. <h3>Results</h3> A total of 139 patients were analyzed, 31 (22%) with CSPC and 107 (78%) with CRPC (78%). Median follow-up after SBRT was 49 months (range 6.7 to 143.5 months). 124 patients (89%) were treated with SBRT at multiple sites for their oligometastatic disease and most treated lesions (96.7%) were osseous metastases. In addition, 76% of CRPC and 58% of CSPC patients had previously received chemotherapy (p=0.09) and 82% of CRPC and 48% of CSPC had previously received a second-generation antiandrogen (p<0.001). The median BPFS defined by PCWG-3 was 48.1 months (95% CI 10.5-NR) in CSPC versus 20.5 months (95% CI 17.5-34.4) in CRPC (p=0.2). DPFS and LPFS were very similar, with excellent long-term local control in both CSPC and CRPC (75% LPFS versus 38% DPFS at 2 years, 66% LPFS and 19% DPFS at 4 years). Overall survival was significantly longer in CSPC patients compared to CRPC patients (median OS not reached versus 64.4 months, p=0.016). Overall survival after radiotherapy trended worse among patients with CRPC previously exposed to chemotherapy (death HR 2.32, p=0.075) or second-generation antiandrogen (death HR 2.1, p=0.12) as would be expected; this trend was not present in CSPC. <h3>Conclusion</h3> In our study of oligometastatic prostate cancer patients treated with SBRT to a site of metastatic disease, patients with CSPC had better outcomes for progression-free survival and overall survival compared to CRPC patients. Pre-treatment with chemotherapy or second-generation antiandrogens did not significantly impact overall survival in patients with CSPC. Local control was excellent in both CSPC and CRPC, suggesting that highly sensitive imaging modalities may best select patients for effective SBRT.

Nodal and osseous oligometastatic prostate cancer: a cohort including the introduction of PSMA-PET/CT-guided stereotactic and hypofractionated radiotherapy with elective nodal therapy

PurposeOligometastatic prostate cancer is heavily investigated, and conventionally fractionated elective nodal treatment appears to increase biochemical relapse-free (bRFS) survival. The novelty of this report is to present elective nodal radiotherapy (ENRT) with simultaneous integrated boost with stereotactic (SBRT) or hypofractionated radiotherapy (HoFRT) for tolerance and for bRFS which we compared with SBRT of the involved field (IF) only.Materials and methodsPatients between 2018 and 2021 with and oligometastatic prostate cancer treated with SBRT or hypofractionation were eligible. A radiobiologically calculated simultaneous integrated boost approach enabled to encompass elective nodal radiotherapy (ENRT) with high doses to PSMA-positive nodes. A second group had only involved field (IF) nodal SBRT.ResultsA total of 44 patients with 80 lesions of initially intermediate- (52%) or high-risk (48%) D’Amico omPC were treated with SBRT to all visible PSMA-PET/CT lesions and 100% of the treated lesions were locally controlled after a median follow-up was 18 months (range 3–42 months). Most lesions (56/80; 70%) were nodal and the remainder osseous. Median bPFS was 16 months and ADT-free bPFS 18 months. ENRT (31 patients) versus IF (13 patients) prevented regional relapse more successfully. At univariate analysis, both initial PSA and length of the interval between primary diagnosis and biochemical failure were significant for biochemical control. Treatment was well tolerated and only two patients had toxicity ≥ grade 3 (1 GU and 1 GI, each).Discussion/conclusionSBRT and hypofractionated radiotherapy at curative doses with ENRT was more effective to delay ADT than IF, controlled all treated lesions and was well tolerated.

A randomized phase Ib/II study of intermittent androgen deprivation therapy plus nivolumab with or without interleukin-8 blockade in men with hormone-sensitive prostate cancer (MAGIC-8).

5082 Background: Immunotherapy has limited efficacy in castration-resistant prostate cancer. Androgen deprivation therapy (ADT) has significant immunomodulatory effects and initially induces a complex immune infiltrate before castration-resistance develops. However, ADT also recruits immunosuppressive myeloid cells to the tumor microenvironment by increasing interleukin-8 (IL-8). We conducted a phase Ib/II clinical trial of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC). We hypothesized that anti-PD-1 (nivolumab) +/- anti-IL-8 (BMS-986253) given at the time of castration could induce anti-tumor immune responses and decrease disease progression. Methods: MAGIC-8 was a multicenter, phase Ib/II study evaluating nivolumab +/- BMS-986253 combined with a short course of degarelix acetate in patients with recurrent CSPC and rapid PSA doubling time (≤ 12 mos). In the Phase Ib portion, patients were treated with nivolumab (480mg Q4W) for 8 wks followed by nivolumab plus degarelix for an additional 16 wks. In the phase II portion, patients were randomized 1:2 to nivolumab + degarelix (Arm A) versus nivolumab + BMS-986253 (2400mg Q2W) + degarelix (Arm B). The primary endpoints were PSA recurrence at 10 mos following randomization and safety. Key secondary endpoints included biochemical recurrence-free survival (bPFS), time to recovery of testosterone (&gt; 150ng/dl), and bPFS after recovery of testosterone. Results: Between October 16, 2019 and March 9, 2021, 59 patients were enrolled. The first 15 patients were treated on Arm A followed by 1:2 randomization to Arm A (N = 15) versus Arm B (N = 29). Median follow up was 11.6 mos at the data cutoff (1/24/22). Patients treated on Arm A had a significantly lower rate of PSA relapse (17.39%) at 10 mos compared to historical controls (p = &lt; 0.001), including a subgroup of patients (6.67%) with recovery of testosterone and no PSA relapse at &gt; 2 years of follow up. Median time-to-recovery of testosterone was 12.7 mos, median bPFS was 14.0 mos and median bPFS after recovery of testosterone was 5.5 mos. In Arm B, there was no difference in PSA relapse at 10 mos (35%, p = 0.09), median time-to-recovery of testosterone, median bPFS and median bPFS after recovery of testosterone compared to historical controls. Treatment in both arms was well tolerated with a lower rate of grade 3-4 treatment-related adverse events in Arm B compared to Arm A (3.5% vs 12.9%). Conclusions: A short course of ADT plus nivolumab may decrease the rate of PSA relapse and lead to durable long-term responses after recovery of testosterone in a subset of patients. These data support further evaluation of combining nivolumab with ADT in CSPC. Although the addition of BMS-986253 did not improve rate of PSA relapse, we observed significantly less toxicity with the addition of IL-8 inhibition. Clinical trial information: NCT03689699.

Survival Outcomes and Pattern of Relapse After SABR for Oligometastatic Prostate Cancer.

IntroductionThe addition of stereotactic ablative radiotherapy (SABR) to standard of care for patients with oligometastatic prostate cancer has the potential of improving survival and delaying further metastases. The primary aim of this analysis is to report survival outcomes and pattern of recurrence of patients with hormone-sensitive (HSPC) and castrate-resistant (CRPC) oligometastatic prostate cancer treated with SABR.MethodsThis is a single-center retrospective study of patients with oligometastatic prostate cancer treated in Iridium Network between 2014 and 2018. All patients with oligometastatic (≤3 active lesions) HSPC and CRPC treated with SABR were included. Data were collected using electronic records. Patterns of first progression following SABR were reported. Kaplan-Meier methods were used to determine survival outcomes.ResultsEighty-seven men received SABR to 115 metastases. Nineteen patients were castrate-resistant and 68 hormone-sensitive at the time of SABR. Median follow-up was 41.6 months. In 25% of patients, no decline from baseline PSA was recorded. Median bPFS was 11.7 months (95% CI 7.6 - 18.3) for HSPC as well as CRPC (95% CI 6.4 - 24.0) (p=0.27). Median DMFS was 21.8 (95% CI 16.9 - 43.2) versus 17.6 months (95% CI 6.7 - 26.2) for HSPC versus CRPC, respectively (p=0.018). Median OS was 72.6 months (95% CI 72.6 – not reached) for HSPC and not reached for CRPC (95% CI 35.4 months – not reached) (p=0.026). For the subgroup of oligorecurrent HSPC, short-term androgen-deprivation therapy was associated with improved bPFS (median 6.0 vs. 18.3 months, HR 0.31, p<0.001) and DMFS (median 15.8 vs 29.6 months, HR 0.5, p=0.06). Information on pattern of relapse was retrieved for 79 patients: 45% (36/79) of these patients were long-term disease-free (>18 months), 28% (22/79) of patients wmere oligoprogressive (≤3 new lesions) and 27% (21/79) developed a polymetastatic relapse.ConclusionIn this cohort, oligometastatic HSPC showed potential benefit from SABR with a median DMFS of 21.8 months. Well-selected patients with oligometastatic CRPC may also benefit from SABR. For patients with metachronous and repeat oligorecurrent HSPC, combining SABR with short-term androgen-deprivation therapy was associated with improved bPFS and DMFS. Overall, 36/87 (41%) of patients were still free from clinical relapse at 18 months.

AbiDex: Retrospective U.K. analysis of steroid switching in patients with progression of mCRPC treated with abiraterone acetate.

114 Background: Abiraterone acetate (AA) is a mainstay of treatment for metastatic castrate resistant prostate cancer (mCRPC). Due to inhibition of glucocorticoid synthesis, AA can cause mineralocorticoid excess which is suppressed by the co-administration of a glucocorticoid. Prednisolone (P) is widely used to counter the side effects of AA. There is an expanding body of retrospective evidence that dexamethasone (D) may be a more suitable partner for AA and on biochemical progression with AA+P, a ‘steroid switch’ to AA+D may be efficacious in regaining PSA control. Methods: Retrospective analysis patients treated with AA at a UK, tertiary cancer centre, were included to a data cutoff of 28th April 2021. Those who had undergone a steroid switch were identified and baseline data of demographics and clinical history were collected, as well as biochemical and radiological data whilst on AA. Analysis was conducted using SPSS. Biochemical progression free survival (bPFS) analysis was conducted using the Kaplan-Meier U test. Response steroid switch and survival when compared to potential predictive factors was analysed using binomial logistic and Cox regression models. Results: Thirty-three patients were treated with AA and received a steroid switch, AA+P(5mg BD) to AA+D(0.5mg OD) between 2012 and data cutoff. The median age at diagnosis was 71, the majority had Gleason 7 disease (7-10). Nine patients had received prior Docetaxel chemotherapy. Four patients failed to respond to AA+P; three of which achieved a biochemical response after steroid switch. Following switch to AA+D, 24 (73%) of patient achieved a rebound biochemical response after progression on AA+P, of those who achieved a response, 4 (12%) achieved a &gt;30% reduction in PSA, and 12( 36%) achieved a &gt;50% reduction in PSA. The median bPFS before and after steroid switch was 9 (AA+P) vs 19 (AA+P&amp;+D) months (HR 0.28; 95% CI 0.16-0.51; p&lt;.001). Analysis of response to steroid switch showed no significant correlation between response and any investigated clinical factor. A raised ALP(&gt;130U/L) on commencing AA+D predicted for a poorer bPFS (HR 2.4; 95% CI 1.1-5.5; p=0.038) and OS (HR 3.2; 95% CI 1.2-8.5; p=0.02). Conclusions: A steroid switch from AA+P to AA+D on biochemical progression is gaining more evidence as a beneficial technique to improve duration of treatment on AA. This study again suggests that bPFS is significantly improved by a steroid switch from P to D. Although negative in this study, several predictive models have been reported to help clinical selection of who may benefit most from a switch. Despite this, there is no official guidance or consensus on when and how a steroid switch should be used and whether this improves overall survival of those with mCRCP. Further randomised, prospective studies are needed to to better define the utility of AA+D, including in the first line setting.

Efficacy of neoadjuvant docetaxel + cisplatin chemo-hormonal therapy versus docetaxel chemo-hormonal therapy in patients with locally advanced prostate cancer with germline DNA damage repair gene alterations

Purpose:To assess the efficacy and safety of neoadjuvant docetaxel + cisplatin chemotherapy with androgen deprivation therapy for the treatment of locally advanced prostate cancer (PCa) in patients harboring germline DNA damage repair genes (gDDR) defects.Methods:We conducted a prospective observational study in patients with locally advanced PCa confirmed with gDDR defects through next-generation sequencing. All patients received either docetaxel + cisplatin (platinum-group) or docetaxel chemo-hormonal therapy (docetaxel group) followed by radical prostatectomy with extended lymphadenectomy. The primary end point was biochemical progression-free survival (bPFS) and secondary end points include postoperative pathological response and safety assessment during the study period.Results:A total of 36 patients were included in the study, among whom 14 and 22 patients received docetaxel + cisplatin and docetaxel treatment, respectively. Down-staging of Tumor (T), Nodes (N), and Metastasis (M) stages was observed in 11 (78.57%) and 9 (40.9%) patients (p = 0.041), respectively, in the docetaxel + cisplatin group and docetaxel group. The median bPFS was 7.76 months (95% CI 0.770–14.748) and not reached in the docetaxel group and docetaxel + cisplatin group, respectively. bPFS was significantly longer in the docetaxel + cisplatin group (p = 0.039) with a hazard ratio of 0.386 (95% CI 0.151–0.987, p < 0.05). Furthermore, one patient discontinued docetaxel + cisplatin after second cycle due to severe liver insufficiency which was confirmed as viral hepatitis A and no significant perioperative complications was observed in either group.Conclusion:This study suggests that cisplatin may increase docetaxel anticancer activity with tolerable safety profile in patients with locally advanced PCa carrying gDDR defects in the neoadjuvant setting, a hypothesis which will require prospective, randomized confirmation.

Predictors of efficacy of corticosteroid switching from abiraterone plus prednisone to dexamethasone in patients with metastatic castration-resistant prostate cancer.

Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate (AA). We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018. All cases received AA plus prednisone as first-line therapy during mCRPC. Primary end points were biochemical progression-free survival (bPFS) and overall survival (OS). The risk groups were defined based on multivariate analysis. A total of 42 (41.6%) and 25 (24.8%) patients achieved 30% and 50% decline in prostate-specific antigen (PSA), respectively, after corticosteroid switching. The median bPFS and median OS on AA plus dexamethasone were 4.9 (95% confidence interval [CI]: 3.7–6.0) months and 18.8 (95% CI: 16.2–30.2) months, respectively. Aldo-keto reductase family 1 member C3 (AKR1C3) expression (hazard ratio [HR]: 2.15, 95% Cl: 1.22–3.80, P = 0.008) and baseline serum alkaline phosphatase (ALP; HR: 4.95, 95% Cl: 2.40–10.19, P < 0.001) were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS. Only baseline serum ALP >160 IU l−1 (HR: 3.41, 95% Cl: 1.57–7.38, P = 0.002) together with PSA level at switch ≥50 ng ml−1 (HR: 2.59, 95% Cl: 1.22–5.47, P = 0.013) independently predicted poorer OS. Based on the predictive factors in multivariate analysis, we developed two risk stratification tools to select candidates for corticosteroid switching. Detection of serum ALP level, PSA level, and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.

Outcomes of metastasis-directed therapy of bone oligometastatic prostate cancer

BackgroundThe aim of this work was to investigate the outcome of metastasis-directed radiotherapy (MDT) in prostate cancer patients with bone metastases following current ESTRO/EORTC subclassifications for oligometastatic disease.MethodsClinical data of 80 consecutive oligometastatic patients with 115 bone lesions receiving MDT between 2011 and 2019 were retrospectively evaluated. Hormone-sensitive (77.5%) and castrate-resistant (22.5%) patients were included. MDT was delivered with conventional fractionated or stereotactic body radiotherapy (SBRT) techniques. Kaplan–Meier method, log rank test, as well as Cox regression were used to calculate local control (LC) and biochemical and clinical progression-free survival (bPFS/cPFS).ResultsAt the time of MDT 31% of patients had de-novo synchronous oligometastatic disease, 46% had de-novo metachronous oligorecurrence after primary treatment and 23% had either de-novo oligoprogressive disease, repeat oligometastatic disease or induced oligometastatic disease. The median BED3 was 93.3 Gy (range 75.8–95.3 Gy). Concomitant ADT was administered in 69% of patients. After a median follow-up of 23 months the median bPFS and cPFS were 16.5 and 21.5 months, respectively. The 2-year LC rate was 98.3%. In multivariate analysis, age ≤ 70 (HR = 2.60, 95% CI 1.20–5.62, p = 0.015) and concomitant ADT (HR = 0.26, 95% CI 0.12–0.58, p = 0.001) significantly correlated with cPFS. Category of oligometastatic disease and hormone-sensitivity were predictive for cPFS in univariate analysis. Of 45 patients with biochemical relapse, nineteen patients (42.2%) had repeat oligometastatic disease. Fourteen patients (31%) underwent a second course of MDT. No patients experienced grade ≥ 3 toxicities.ConclusionsMDT is safe and offers high local control rates in bone oligometastases of prostate cancer. At 2 years after treatment, more than 2 out of 5 patients are progression-free.Trial registration Retrospectively registered.

Efficacy of PSMA PET-Guided Radiotherapy for Oligometastatic Castrate-Resistant Prostate Cancer

PurposeTo assess the outcome of radiotherapy (RT) to all PSMA ligand positive metastases for patients with castrate-resistant prostate cancer (mCRPC).Patients and methodsA total of 42 patients developed oligometastatic mCRPC and received PSMA PET-guided RT of all metastases. The main outcome parameters were biochemical progression-free survival (bPFS), and second-line systemic treatment free survival (SST-FS).ResultsA total of 141 PSMA ligand-positive metastases were irradiated. The median follow-up time was 39.0 months (12-58 months). During the follow-up five out of 42 (11.9%) patients died of progressive mPCa. Five out of 42 (11.9%) patients showed no biochemical responses and presented with a PSA level ≥10% of the baseline PSA at first PSA level measurement after RT and were classified as non-responders. The median PSA level before RT was 4.79 ng/mL (range, 0.4-46.1), which decreased significantly to a median PSA nadir level of 0.39 ng/mL (range, <0.07-32.8; p=0.002). The median PSA level at biochemical progression after PSMA ligand-based RT was 2.75 ng/mL (range, 0.27-53.0; p=0.24) and was not significantly different (p=0.29) from the median PSA level (4.79 ng/mL, range, 0.4-46.1) before the PSMA ligand-based RT. The median bPFS was 12.0 months after PSMA ligand PET-based RT (95% CI, 11.2-15.8) and the median SST-FS was 15.0 months (95% CI, 14.0-21.5).ConclusionIn well-informed and closely followed-up patients, PSMA PET-guided RT represents a viable treatment option for patients with oligometastatic mCRPC to delay further systemic therapies.

The prognostic nomogram including MRI for locally advanced prostate cancer treated by radical prostatectomy.

To establish the prognostic nomogram for locally advanced prostate cancer (LAPC) patients treated by radical prostatectomy (RP) based on clinical and multiparametric-MRI (mp-MRI) metrics. One hundred and twenty-one patients diagnosed with LAPC were included in this study. They were all examined by mp-MRI within one week before surgery and treated by RP (36 with RP alone, 48 with neoadjuvant hormonal therapy (NHT) and 37 with neoadjuvant chemohormonal therapy (NCHT)). The biochemical progression-free survival (bPFS) was analyzed by Kaplan-Meier method. Univariate and multivariate analysis were used to determine prognostic factors that were related with bPFS. The prognostic nomogram was established by factors that were significant in multivariate analyses. The median bPFS had significant difference in the subgroup of treatment (RP alone: 2 [0.00-5.04] vs. NHT: 9.3 [6.746-11.854] vs. NCHT: 11.17 [0.000-25.075] months [Log rank p < .001]), the subgroup of hyperintensity within prostate in DWI (negative: 15.97 [11.202-20.731] vs. positive: 5.2 [2.952-7.448] months [Log rank p < .001]) and the subgroup of pelvic lymph node metastasis (negative: 10.2 [8.404-11.996] vs. unilateral: 4.43 [0.000-11.086] vs. Bilateral: 1.83 [0.636~3.031] [Log rank p < .001]). The method of treatment (hazards ratio [HR], 0.566; 95% confidence interval [CI], 0.356-0.899; p = .016), hyperintensity within prostate in DWI (HR, 2.539; 95% CI, 1.349-4.779; p = .004) and the metastasis burden of pelvic lymph node (HR, 2.492; 95% CI, 1.645-3.777; p < .001) were identified as independent predictors with significance in multivariable Cox regression analysis. The nomogram was established based on these three factors. We established a nomogram based on three significant prognosis factors including the neoadjuvant therapeutic schedule, hyperintensity within prostate in DWI and the metastasis burden of pelvic lymph nodes, which were associated with the clinical outcomes in LAPC patients after surgery.

Outcomes of Initial Therapy for Synchronous Brain Metastases from Extensive Stage Small Cell Lung Cancer

Small cell lung cancer (SCLC) has a propensity for brain metastases, which is associated with poor prognosis. 20% of SCLC patients have synchronous brain metastases at initial diagnosis. We sought to determine predictors of overall survival (OS) and brain progression-free survival (bPFS) in SCLC patients with synchronous brain metastases treated with chemotherapy (chemo) and/or whole brain radiation (WBRT). Among the 836 SCLC patients treated at a single institution between 1998 and 2018, 109 patients with synchronous brain metastases at initial diagnosis were included in this retrospective analysis. Survival was estimated with the Kaplan-Meier method. Factors predictive of OS and bPFS were analyzed using Cox proportional hazards regression modeling and log-rank testing. Of the 109 patients, 18 received chemo without WBRT, 15 received WBRT without chemo, and 76 received chemo and WBRT. Of the 76 patients who received chemo and WBRT, 8 started both concurrently, 35 received chemo first, and 33 received WBRT first. Median WBRT dose was 30 Gy in 10 fractions. The median number of brain lesions at diagnosis was 3, and the median size of the largest metastasis was 2.0 cm. Median OS for the entire cohort was 9 months and median bPFS was 8.4 months. OS was 30.3% at 1 year and 14.4% at 2 years. Increased number of brain lesions was significantly associated with decreased OS. 59 patients presented with neurological symptoms, which was not associated with OS or bPFS. 46 patients had isolated brain metastases (no extracranial metastases), which was not associated with improved OS (p = 0.061) or bPFS (p = 0.17) compared to patients with other extracranial metastatic disease. The median age at diagnosis was 63. Patients younger than 63 years old had improved OS compared to patients age 63 or older, but not bPFS. Patients who received chemo and WBRT had improved OS compared to those who had either chemo or WBRT alone (p<0.001), but there was no difference in bPFS (p = 0.34). There was no significant difference in OS or bPFS depending on the sequence of therapy initiation. For patients who had chemo followed by WBRT, the median time between start of chemo and start of radiation was 103 days (range 6 – 182 days), which was not significantly associated with OS or bPFS. 13 patients received upfront brain metastasis resection, which was associated with improved OS but not bPFS compared to those who did not have surgery. 14 patients received SRS or partial brain radiation as part of their initial therapy, which was not significantly associated with OS or bPFS. 15 patients received salvage brain radiation after WBRT failure, which was associated with improved OS compared to those who did not have salvage radiation (25.5 months vs 8.0 months, p<0.001). The combination of chemo and WBRT was associated with improved OS compared to either modality alone. The sequence of treatment was not associated with OS or bPFS. Shorter time to WBRT after chemo was not significantly associated with OS or bPFS.

Efficacy of repeated PSMA PET-directed radiotherapy for oligorecurrent prostate cancer after initial curative therapy

PurposeTo assess the outcome of prostate cancer (PCa) patients diagnosed with oligorecurrent disease and treated with a first and a second PSMA (prostate-specific membrane antigen ligand) PET(positron-emission tomography)-directed radiotherapy (RT).Patients and methodsThirty-two patients with oligorecurrent relapse after curative therapy received a first PSMA PET-directed RT of all metastases. After biochemical progression, all patients received a second PSMA PET-directed RT of all metastases. The main outcome parameters were biochemical progression-free survival (bPFS) and androgen deprivation therapy-free survival (ADT-FS). The intervals of BPFS were analyzed separately as follows: the interval from the last day of PSMA PET-directed RT to the first biochemical progression was defined as bPFS_1 and the interval from second PSMA PET-directed RT to further biochemical progression was defined as bPFS_2.ResultsThe median follow-up duration was 39.5 months (18–60). One out of 32 (3.1%) patients died after 47 months of progressive metastatic prostate cancer (mPCa). All patients showed biochemical responses after the first PSMA PET-directed RT and the median prostate-specific antigen (PSA) level before RT was 1.70 ng/mL (0.2–3.8), which decreased significantly to a median PSA nadir level of 0.39 ng/mL (range <0.07–3.8; p = 0.004). The median PSA level at biochemical progression after the first PSMA PET-directed RT was 2.9 ng/mL (range 0.12–12.80; p = 0.24). Furthermore, the PSA level after the second PSMA PET-directed RT at the last follow-up (0.52 ng/mL, range <0.07–154.0) was not significantly different (p = 0.36) from the median PSA level (1.70 ng/mL, range 0.2–3.8) before the first PSMA PET-directed RT. The median bPFS_1 was 16.0 months after the first PSMA PET-directed RT (95% CI 11.9–19.2) and the median bPFS_2 was significantly shorter at 8.0 months (95% CI 6.3–17.7) after the second PSMA PET-directed RT (p = 0.03; 95% CI 1.9–8.3). Multivariate analysis revealed no significant parameter for bPFS_1, whereas extrapelvic disease was the only significant parameter (p = 0.02, OR 2.3; 95% CI 0.81-4.19) in multivariate analysis for bPFS_2. The median ADT-FS was 31.0 months (95% CI 20.1–41.8) and multivariate analysis showed that patients with bone metastases, compared to patients with only lymph node metastases at first PSMA PET-directed RT, had a significantly higher chance (p = 0.007, OR 4.51; 95% CI 1.8–13.47) of needing ADT at the last follow-up visit.ConclusionIf patients are followed up closely, including PSMA PET scans, a second PSMA PET-directed RT represents a viable treatment option for well-informed and well-selected patients.

Efficacy and toxicity outcomes for patients treated with focal salvage high dose rate brachytherapy for locally recurrent prostate cancer

IntroductionIsolated local recurrence of prostate cancer following primary radiotherapy or brachytherapy may be treated with focal salvage high dose rate brachytherapy, although there remains an absence of high quality evidence to support this approach. MethodsMen with prostate cancer treated consecutively between 2015 and 2018 using 19 Gy in a single fraction high dose rate brachytherapy (HDR) for locally recurrent prostate cancer were identified from an institutional database. Univariable analysis was performed to evaluate the relationship between patient, disease and treatment factors with biochemical progression free survival (bPFS). Results43 patients were eligible for evaluation. Median follow up duration was 26 months (range 1–60). Median bPFS was 35 months (95% confidence interval 25.6–44.4). Kaplan-Meier estimates for bPFS at 1, 2 and 3 years post salvage were 95.2%, 70.6% and 41.8% respectively. On univariable Cox regression analysis, only nadir PSA was significantly associated with bPFS although the majority of patients were also treated with androgen deprivation therapy. Only one late grade 3 genitourinary toxicity was observed. ConclusionFocal salvage HDR brachytherapy may provide good biochemical control with a low risk of severe toxicity. Further evaluation within clinical trials are needed to establish its role in the management of locally recurrent prostate cancer.

871P - Adding ADT to PSMA-PET/CT-guided SBRT for oligometastatic prostate cancer improves distant progression-free survival

BackgroundTo report on the local response (LR), biochemical progression-free (bPFS) and distant-progression free (DPFS) survival after stereotactic body radiotherapy (SBRT) for bone and lymph node prostate cancer oligometastases. MethodsWithin the context of a prospective SBRT trial for oligometastases (NCT03486431), 54 bone and lymph node oligometastases, all detected on PSMA-PET/CT, were irradiated in 40 prostate cancer patients between July 2017 and December 2018. Of these patients, 35 had hormone-sensitive and 5 had castration-resistant disease. Short-term concomitant ADT was recommended in all hormone-naïve patients but decided in consultation with the patient. Ultimately, 20 patients received ADT while 20 did not. The two groups were well balanced, with no significant differences in age, Gleason score, PSA, lesion type, number or timing of metastases, and fractionation schedule. All patients received a PSMA-PET/CT at 6 months after SBRT. PSMA-RADS v1.0 was used to categorize the response of the treated lesion. Quality-of-life (QOL) scoring was performed using the EORTC QLQ-C30 questionnaire at baseline, 3 and 6 months. ResultsMedian follow-up for all patients was 9.6 months (IQR 6.3 – 12.9 months). Up till now, 42 lesions could be reevaluated at 6 months after SBRT with PSMA-PET/CT, of which 30 showed complete response, 8 partial response and 4 stable disease. No symptomatic or local progression was observed in the irradiated lesions. There was no statistically significant influence of ADT, fractionation, type of lesion or lesion size on LR. Patients who received ADT had significantly improved bPFS (median bPFS of 6.9 months versus median not reached; p=0.0017) and DPFS (median DPFS of 6.8 months versus 17.3 months; p=0.0021). We did not observe any clinically relevant changes in QOL scores between the patients who received ADT versus those who refused. Overall, QOL scores remained stable for both groups at baseline, 3 and 6 months. ConclusionsThese prospective data, although non-randomized, suggest that oligometastatic prostate cancer patients treated with SBRT could potentially benefit from short-term ADT. Longer follow-up will determine if ADT simply delays progression or truly alters the course of the disease. Clinical trial identificationNCT03486431. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Neoadjuvant chemohormonal therapy combined with radical prostatectomy and extended PLND for very high risk locally advanced prostate cancer: A retrospective comparative study

ObjectiveDocetaxel has been shown to be an effective chemotherapy agent when combined with androgen deprivation therapy for hormone sensitive metastatic prostate cancer (CaP). Since very high risk CaP has a high rate of occult metastatic disease and early recurrence, we hypothesize that patients with very high risk locally advanced CaP may benefit from docetaxel-based neoadjuvant chemohormonal therapy (NCHT). Thus, we conducted a retrospective study to identify the outcome of these patients treated with NCHT followed by radical prostatectomy (RP). Patients and MethodsWe retrospectively analyzed data from 177 consecutive patients who had very high risk locally advanced CaP between March 2014 and July 2017. Patients received 3 different therapies: (i) 60 men in NCHT group, (ii) 73 men in neoadjuvant hormonal therapy (NHT) group, and (iii) 44 men received immediate RP without neoadjuvant therapy (No-NT group). Surgical outcomes were analyzed and survival differences were compared by the Kaplan-Meier method. ResultsThe NCHT group had statistically significant higher preoperative Prostate-Specific Antigen (PSA) (P < 0.002), higher Gleason score (P < 0.002), and more advanced clinical stage (P < 0.001) than other groups. After RP, 81% (42/52) of patients in NCHT group, 73% (51/70) of patients in NHT group, and 48% (21/44) of patients in No-NT group achieved an undetectable PSA (P < 0.001). A total of 14% (6/42) patients achieving a postoperative undetectable PSA experienced biochemical recurrence in the NCHT group, with median biochemical progression-free survival (bPFS) time of 19 months; 47% (24/51) experienced biochemical recurrence in the NHT group, with median bPFS time of 13 months; 81% (17/21) experienced biochemical recurrence in the No-NT group, with median bPFS time of 9 months (P < 0.001). The median follow-up time of 3 groups was 12.5 months in the NCHT group, 18.3 months in the NHT group, and 22.8 months in the No-NT group (P = 0.01). ConclusionDespite having poorer prognostic factors, the NCHT group had better bPFS time after surgery compared to NHT and No-NT groups. Randomized controlled investigations are needed to validate these results and further follow-up is required for survival endpoints.

Radiation Therapy in the Definitive Management of Oligometastatic Prostate Cancer: The Johns Hopkins Experience

Purpose:The use of radiation therapy (RT) in consolidating oligometastatic prostate cancer (OPCa) is a rapidly evolving treatment paradigm. We review our institutional experience using metastasis-directed therapy in the definitive management of men with OPCa.Methods and Materials:Patients with OPCa treated with definitive RT were included. The Kaplan-Meier method and multivariable Cox regression analysis were performed to assess biochemical progression-free survival (bPFS) and time to next intervention. Cumulative incidence functions were used to calculate rates of local failure. Toxicity was assessed using Common Terminology Criteria for Adverse Events (version 4).Results:This study analyzed 156 patients with OPCa and 354 metastatic lesions with median follow-up of 24.6 months. Of 150 patients with toxicity data, 53 (35%) experienced acute grade 1 toxicity, 8 (5%) had grade 2, and none had grade 3 toxicity. Only 13 patients (9%) had late toxicities. At 24 months, the cumulative incidence of local failure was 7.4%. Median bPFS for the entire cohort was 12.9 months and 52% at 1 year. On multivariable analysis, factors associated with prolonged bPFS were periRT androgen deprivation therapy (ADT), lower gross tumor volume, and hormone-sensitive (HS) OPCa. Median time to next intervention, including repeat RT, was 21.6 months. Median bPFS for men with HS prostate cancer was 17.2 months compared with 7.2 months in men with castrate-resistant OPCa (P < .0001), and cumulative incidence of local failure at 24 months was lower with HS OPCa (4.8% vs 12.1%; P = .034). We analyzed 28 men with HS OPCa treated with a course of peri-RT ADT (median, 4.3 months) with recovery of testosterone. At a median follow-up of 33.5 months, 20 patients had not developed bPFS, median bPFS had not been reached, and 24-month bPFS was 77%.Conclusions:Metastasis-directed therapy can be effective across a wide range of OPCa subtypes, but with differential efficacy. Further study is warranted to investigate the use of RT across the wide range of patients with OPCa.

Dexamethasone in pretreated men with metastatic castration-resistant prostate cancer (mCRPC): A prospective study.

239 Background: Corticosteroids have demonstrated activity in men with mCRPC. Previous data suggested that dexamethasone (D) can induce PSA responses when introduced after progression in mCRPC men receiving AR axis targeted drugs and/or prednisone (P). Methods: We prospectively tested P to D switch or D addition at PSA progression in 43 men with mCRPC with PSA progression and stable clinical disease. Baseline characteristics of the patients, time to castration resistance (TTCRPC), response to previous treatment, PSA response during D 0.5 mg/day and biochemical progression-free-survival (bPFS) after D initiation were recorded. Results were assessed using the Fisher’s exact test to compare variables. Results: Data from 43 patients were prospectively collected: 29 (67%) had been treated with abiraterone (AA) + P, 11 (26%) with enzalutamide (ENZ) and 3 (7%) with other treatments. At progression, 27 patients (63%) switched from P to D while continuing AA, 9 (21%) stopped their treatment and began D alone and 7 (21%) received D added to ENZ. Median age was 75 (70-79.5) and median bPFS with previous treatment was 17 months (6.75-22.25). After D initiation, 28% of patients had a PSA decrease ≥ 30% and the median bPFS was 4 months (2-6). The median bPFS was non-statistically different in patients with previous response to AR axis targeted drugs ≥ 6 months (4 [2-6] vs 1 [1-2] months; p-value = 1) and in those with TTCRPC ≥12 months (4 months [2-7.5] vs. 2 [1.5-2]; p-value = 0.3). Eleven patients (26%) had a bPFS ≥ 6 months and 5 (12%) had a bPFS ≥ 12 months. All long D responders (bPFS ≥ 6 months) had a TTCRPC ≥ 12 months, 10/11 patients had a previous PFS ≥ 6 months on AA or ENZ. None of the 2 patients (4.6%) with primary resistance to AA, responded to switch from P to D. Conclusions: D alone or in combination with previous AR axis targeted agents has activity in mCRPC men, with long responders observed amongst those with previous long response to ADT or to next generation AR axis targeting.

Efficacy of antiangiogenic renal neoplasm with bone metastasis: A mono-institutional study in France.

610 Background: Although bone metastases occur frequently in metastatic renal cell carcinoma (mRCC) and represent approximatively 20-30% of the different sites of metastases, few studies have assessed the prognostic impact of these metastatic sites. In this context, the aim of our study was to evaluate the efficiency of antiangiogenic (AA) treatments in this particular site Methods: A retrospective review of patients with mRCC and bone metastases, treated with a first line of antiangiogenic therapy at the Centre Leon Berard (CLB) was conducted between January 2010 and November 2016. In order to identify a differential treatment effect according to the metastatic site, we assessed the bone progression-free survival (bPFS) defined as the time from the first day of 1st line AA to the date of bone progression or death; and extra bone PFS (ebPFS), defined as the time from the 1st day of 1st line AA to the date of extra-bone progression or death. The association between survival and potential prognosis factor, including metastases location was assessed using log-rank test for univariate analysis Results: A total of 200 patients (146 men; mean age 57,9 years; range 21-86) were analysed and the most common first line AA used was Sunitinib (147; 73,5%). Median PFS at the first AA line was 7,4 months (95% confidence interval (CI) = 6,1-9,2months). Median bPFS was higher than the median of extra bone metastasis PFS (11 months (95% CI = 9-14 months) versus 9 months (95% CI = 8 to 12 months). Other factors have a pejorative impact on the PFS such as sarcomatoid component, non clear cell RCC, Karnofsky index, and the presence of renal thrombus Conclusions: The efficacy of AA was similar on bone and extra-bone metastases, among patients with at least one bone metastasis