CRPC-free Survival Research Articles

Evaluating the effectiveness of cytoreductive surgery in oligometastatic prostate cancer: insights from quantitative analysis and retrospective cohort studies.

Oligometastatic prostate cancer (OmPCa) is characterized by a restricted number of metastatic lesions confined to a limited organ range, presenting a distinct clinical challenge. The role of cytoreductive prostatectomy (CRP) in managing this specific metastatic stage has gained attention but remains controversial. This study aims to assess the effectiveness of CRP in OmPCa by synthesizing outcomes from previous studies and analyzing data from a multicenter, retrospective cohort. We focused on evaluating overall survival (OS), progression-free survival (PFS), cancer-specific survival (CSS), and castration-resistant prostate cancer-free survival (CRPCFS) as primary outcomes. A multicenter comparative retrospective analysis was also conducted on OmPCa patients treated with CRP versus those receiving androgen deprivation therapy (ADT) alone from January 2008 to June 2018. We gathered and analyzed data on patient demographics, tumor characteristics, surgical outcomes, and survival metrics. The quantitative analysis included 18 studies(2 randomized controlled trial (RCT) and 16 non-RCT studies),comprising a total of 1733 patients with oligometastatic prostate cancer,this is the largest number of samples included in the same subject research at present.The pooled analysis demonstrated that cytoreductive surgery was associated with significantly improved OS (hazard ratio [HR]: 0.50, 95% confidence interval[CI]: 0.40-0.60) ,PFS (HR: 0.39, 95%[CI]: 0.27-0.51) ,CSS (HR: 0.44, 95%[CI]: 0.23-0.65) and CRPCFS (HR: 0.48, 95%[CI]: 0.36-0.59) compared to non-surgical management.In addition,OS ,PFS and CRPCFS showed better results in the CRP group in all analyses(RCT and non-RCT).Additionally,in our multicenter retrospective research analysis, 64 patients with oligometastatic prostate cancer were included ,32 underwent CRP (50%), and 32 underwent ADT alone (50%).The median follow-up time was 40.1 (18.9-51.3) months.The OS (P=0.0182), PFS (P=0.0297), and CRPCFS (P=0.0125) had statistical difference between the two matched cohorts.Moreover,we observed 8(25%) cases of perioperative complications, with the most common being urinary incontinence(9.4%). Incorporating CRP alongside ADT in the treatment protocol for OmPCa significantly enhances patient outcomes in terms of OS, PFS, and CRPC-free survival, underscoring the potential benefit of this surgical approach in the specified patient population.

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.

Veterans Affairs seamless phase II/III randomized trial of standard systemic therapy with or without PET-directed local therapy for oligometastatic prostate cancer (VA STARPORT).

TPS5120 Background: The concept of metastasis-directed therapy (MDT) using radiation or surgery for oligometastatic (OM) prostate cancer (pCa) has evolved from an anecdotal hypothesis to a promising approach that may optimally balance toxicity and oncologic efficacy. Recently, there have been multiple smaller phase II randomized trials that have shown a signal of efficacy for MDT in OM pCa. Most studies have compared MDT to observation alone as the control arm, included only recurrent OM patients, and included up to 3-5 sites of metastasis. It is in this context, that the VA STARPORT trial was initiated in 2021 to definitively determine the role of MDT in Veterans with oligorecurrent pCa in 1-5 sites. Yet, the diagnosis and management of metastatic pCa have since evolved. The SABR-COMET-10 trial recently completed enrollment and compares systemic therapy alone or with MDT in patients with 1-10 metastases from various histologies. While pCa PET/CT imaging was only available for Veterans with biochemical recurrence in 2021, PSMA PET/CT now allows for the improved diagnosis of OM in Veterans with de novo pCa—a growing cohort of patients without a clear standard of care. Therefore, to maximize the impact and generalizability of the trial, VA STARPORT has been amended to allow for de novoOM and 1-10 metastases. The primary goal of VA STARPORT is to determine if adding PET-directed local therapy (PDLT) to standard systemic therapy (SST) improves disease control compared to SST alone in Veterans with recurrent and de novooligometastatic pCa. Methods: VA STARPORT is a phase II/III randomized trial open at 18 VA medical centers comparing SST alone (Arm 1) or with PDLT (Arm 2) in Veterans with OM pCa. Key eligibility criteria include recurrent or de novohormone-sensitive metastatic pCa and 1-10 metastatic lesions on any FDA-approved pCa PET/CT. The primary endpoint is castration-resistant prostate cancer-free survival (CRPC-free survival). Secondary endpoints include radiographic PFS, clinical PFS, freedom from index lesion progression, toxicity, quality of life, and prostate cancer-specific and overall survival. SST is delivered using any NCCN guideline-concordant regimen in both arms. PDLT can be either radiation or surgery to all sites of cancer. Regarding local therapy, de novo patients in Arm 1 receive prostate-directed RT, and in Arm 2 receive PDLT to all metastases and the prostate. For recurrent patients in Arm 1 there is no local therapy, while in Arm 2 patients receive PDLT. All participants undergo somatic tumor sequencing using the VA National Precision Oncology Program. Assuming a hazard ratio of 0.60 for SST + PDLT vs SST, two-sided alpha = 0.05 and 90% power, a total of 464 participants will be randomized to generate 166 CRPC-free survival events by the end of the active study phase. Recruitment is ongoing and 150 patients have been enrolled. Clinical trial information: NCT04787744 .

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

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

Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide.

Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.

Predictive Factors of Abiraterone Response in Patients With High-Risk Metastatic Hormone-Sensitive Prostate Cancer

Purpose: This study aimed to identify predictive factors for the response to abiraterone in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC).Materials and Methods: This study analyzed the clinical characteristics of 167 patients with high-risk mHSPC who received abiraterone. Univariate and multivariable Cox proportional hazard regression analyses were conducted to identify predictive factors for castration-resistant prostate cancer (CRPC)-free survival and cancer-specific survival.Results: The mean age at presentation was 71.62±8.12 years. The prostate-specific antigen level was 218 ng/mL (interquartile range, 70–654 ng/mL). Of the 167 patients, 118 (72%) had a biopsy Gleason grade of 5, 43 patients (28.7%) had CRPC, and 30 patients (18.0%) died after a mean follow-up period of 13.5 months. In the multivariable Cox proportional hazard regression analyses for CRPC-free survival, a Gleason grade of 5 (hazard ratio [HR], 2.888; 95% confidence interval [CI], 1.133–7.361; p=0.026) and bone lesions ≥10 (HR, 4.194; 95% CI, 1.760–9.997; p=0.001) were significantly associated with CRPC-free survival. In the multivariable Cox proportional hazard regression analyses for cancer-specific survival, bone lesions ≥10 (HR, 3.185; 95% CI, 1.215–8.348; p=0.001) was significantly associated with cancer-specific survival.Conclusions: Patients with bone lesions ≥10 and Gleason grade of 5 are at higher risk of developing CRPC, and bone lesions ≥10 is at higher risk of cancer-specific survival in high-risk mHSPC treated with abiraterone.

A novel intronic circular RNA circFGFR1int2 up-regulates FGFR1 by recruiting transcriptional activators P65/FUS and suppressing miR-4687-5p to promote prostate cancer progression

Fibroblast growth factor receptor 1 (FGFR1) is a core component of the FGFs/FGFR pathway that activates multiple signalling pathways, including ERK1/2, PI3K/AKT, PLCγ, and NF-κB. Aberrant expression of FGFR1 due to gene amplification, chromosome rearrangement, point mutation, and epigenetic deregulations, have been reported in various cancers. FGFR1 overexpression has also been reported in prostate cancer (PCa), but the underlining mechanisms are not clear. Here we report a novel circular RNA, circFGFR1int2, derived from intron 2 of FGFR1 gene, which is overexpressed in PCa and associated with tumor progression. Importantly, we show that circFGFR1int2 facilitates FGFR1 transcription by recruiting transcription activators P65/FUS and by interacting with FGFR1 promoter. Moreover, we show that circFGFR1int2 suppresses post-transcriptional inhibitory effects of miR-4687-5p on FGFR1 mRNA. These mechanisms synergistically promote PCa cell growth, migration, and invasion. Overexpression of circFGFR1int2 is significantly correlated with higher tumor grade, Gleason score, and PSA level, and is a significant unfavorable prognosticator for CRPC-free survival (CFS) (RR = 3.277, 95% confidence interval: 1.192–9.009; P = 0.021). These findings unravelled novel mechanisms controlling FGFR1 gene expression by intronic circRNA and its potential clinicopathological utility as a diagnostic or therapeutic target.Graphic

Outcomes of Cytoreductive Radical Prostatectomy for Oligometastatic Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography: Results of a Multicenter European Study

BackgroundDe novo oligometastatic prostate cancer (omPCa) on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a new disease entity and its optimal management remains unknown. ObjectiveTo analyze the outcomes of patients treated with cytoreductive radical prostatectomy (cRP) for omPCa on PSMA-PET. Design, setting, and participantsOverall, 116 patients treated with cRP at 13 European centers were identified. Oligometastatic PCa was defined as miM1a and/or miM1b with five or fewer osseous metastases and/or miM1c with three or fewer lung lesions on PSMA-PET. InterventionCytoreductive radical prostatectomy. Outcome measurements and statistical analysisThirty-day complications according to Clavien-Dindo, continence rates, time to castration-resistant PCa (CRPC), and overall survival (OS) were analyzed. Results and limitationsOverall, 95 (82%) patients had miM1b, 18 (16%) miM1a, and three (2.6%) miM1c omPCa. The median prebiopsy prostate-specific antigen was 14 ng/ml, and 102 (88%) men had biopsy grade group ≥3 PCa. The median number of metastases on PSMA-PET was 2; 38 (33%), 29 (25%), and 49 (42%) patients had one, two, and three or more distant positive lesions. A total of 70 (60%) men received neoadjuvant systemic therapy, and 37 (32%) underwent metastasis-directed therapy. Any and Clavien-Dindo grade ≥3 complications occurred in 36 (31%) and six (5%) patients, respectively. At a median follow-up of 27 mo, 19 (16%) patients developed CRPC and eight (7%) patients died. The 1-yr urinary continence rate was 82%. The 2-yr CRPC-free survival and OS were 85.8% (95% confidence interval [CI] 78.5–93.7%) and 98.9% (95% CI 96.8–100%), respectively. The limitations include retrospective design and short-term follow-up. ConclusionsCytoreductive radical prostatectomy is a safe and feasible treatment option in patients with de novo omPCa on PSMA-PET. Despite overall favorable oncologic outcomes, some of these patients have a non-negligible risk of early progression and thus should be considered for multimodal therapy. Patient summaryWe found that patients treated at expert centers with surgery for prostate cancer, with a limited number of metastases detected using novel molecular imaging, have favorable short-term survival, functional results, and acceptable rates of complications.

Clinical Significance of Radical Prostatectomy in Clinical Lymph Node Metastasis in Prostate Cancer.

This study aimed to investigate the role of radical prostatectomy (RP) among clinical nodal metastasis prostate cancer and whether histological confirmation of lymph node metastasis through surgery can help with treatment. After excluding patients with distant metastatic prostate cancer or neoadjuvant androgen deprivation therapy, 42 patients with clinical nodal metastasis who underwent RP at our institution were included in the study. We classified them as having or not having pathological lymph node metastasis. Clinicopathologic data were analyzed in this retrospective chart review. Kaplan-Meier analysis was used to calculate the estimated castration-resistant prostate cancer (CRPC)-free survival, biochemical recurrence (BCR)-free survival, and cancer-specific survival (CSS). There is no significant difference in age, presence of diabetes mellitus, hypertension, BCR time, CRPC time, overall survival, salvage RT rate, and initial prostate-specific antigen level between the two groups. However, there is a significant difference in the pathology N1 group in terms of pathological T stage, pathologic Gleason score, BCR rate, CRPC rate, and CSS. A multivariate Cox proportional hazard regression analysis was used to identify predictors of CRPC-free survival. Patients with pathological lymph node metastasis had a shorter CRPC-free survival [hazard ratio (HR) 4.87; 95% confidence interval (CI) 1.25-19.00, p = 0.02]. Radical prostatectomy can confirm lymph node metastasis. Although pathologic diagnosis has no effect on time to BCR and CPRC, because it affects BCR rate, CRPC rate, and CSS, an accurate pathological diagnosis obtained through surgery is beneficial in the treatment of clinical lymph node metastasis prostate cancer.

Long-Term Prognosis and Treatment Strategy of Persistent PSA After Radical Prostatectomy.

Prostate-specific antigen (PSA) is thought to be undetectable (<0.1 ng/mL) after radical prostatectomy (RP), and persistent PSA (≥0.1 ng/mL) is considered a failure of curative treatment. The study population consisted of 135 patients, all of whom underwent RP for localized prostate cancer, and developed persistent PSA. We set the starting point at the timing of RP, and the endpoints were the development of castration-resistant prostate cancer (CRPC) and cancer-specific survival. Salvage radiation therapy (RT) and androgen deprivation therapy (ADT) were performed in 53 (39.3%) and 64 (47.4%) patients, respectively. Eighteen (13.3%) patients didn't receive any salvage treatment. During the median follow-up of 10.1 years, CRPC was observed in 23 patients, and 6 patients died due to prostate cancer. Kaplan-Meier curves demonstrated the 15-year CRPC-free and cancer-specific survivals were 79.5% and 92.7%, respectively. Cox multivariate analysis demonstrated that seminal vesicle invasion (SVI) (p = 0.007) and nadir PSA ≥1.0 ng/mL (p = 0.002) were independent risk factors for CRPC. Salvage RT demonstrated better cancer control (the 10-and 15-year CRPC-free survival was 94.1% and 94.1%) compared to ADT (75.9% and 58.5%, p = 0.017) after 1:1 propensity score matching. SVI and nadir PSA ≥1.0 ng/mL are independent risk factors for CRPC in patients with persistent PSA after RP. Salvage RT is considered to be the optimal treatment for this condition.

Trends in the use of local intervention for metastatic hormone-naïve prostate cancer: A multicenter retrospective study.

To evaluated the trends of local intervention and their impact on oncological outcomes in metastatic hormone-naïve prostate cancer (mHNPC) in real-world practice. This retrospective multicenter study included 760 patients treated with either androgen deprivation therapy (ADT) without local treatment (no castration-resistant prostate cancer [CRPC] progression within 12 months, control group) or ADT plus local intervention (intervention group) between January 2005 and March 2022. We evaluated the trends in the use of local intervention in patients with mHNPC and factors associated with CRPC-free survival in the intervention group. The use of local intervention gradually increased in combination with upfront combination treatment (docetaxel or androgen receptor axis-targeted agents) for the duration of our study. The number of patients with local intervention combined with upfront treatment was significantly higher in patients with high tumor burden disease than in those with low tumor burden disease. Of the 108 patients who received local intervention, a duration of ≤7 months of initial therapy before local intervention and a level of prostate-specific antigen ≥0.20 ng/mL at the time of local intervention were significantly associated with poor CRPC-free survival. The use of local intervention in combination with upfront therapy to treat mHNPC increased for the duration of our study regardless of the tumor burden. Local intervention in addition to the standard of care for mHNPC may be a feasible treatment option for selected patients, taking into consideration the duration of and response to initial treatment.

MP11-15 THE EFFECT OF A REDUCED DOSE OF APALUTAMIDE ON SKIN-RELATED ADVERSE EVENTS IN ADVANCED PROSTATE CANCER: A MULTICENTER RETROSPECTIVE STUDY

You have accessJournal of UrologyCME1 Apr 2023MP11-15 THE EFFECT OF A REDUCED DOSE OF APALUTAMIDE ON SKIN-RELATED ADVERSE EVENTS IN ADVANCED PROSTATE CANCER: A MULTICENTER RETROSPECTIVE STUDY Kyo Togashi, Mutsu, Japan Shingo Hatakeyama, Ryuji Tabata, Daiji Fujimori, Yohei Kawashima, Toshikazu Tanaka, Teppei Okamoto, Hayato Yamamoto, Takahiro Yoneyama, Yasuhiro Hashimoto Hashimoto, Satoshi Sato, and Chikara Ohyama Kyo TogashiKyo Togashi More articles by this author , Mutsu, Japan Shingo HatakeyamaMutsu, Japan Shingo Hatakeyama More articles by this author , Ryuji TabataRyuji Tabata More articles by this author , Daiji FujimoriDaiji Fujimori More articles by this author , Yohei KawashimaYohei Kawashima More articles by this author , Toshikazu TanakaToshikazu Tanaka More articles by this author , Teppei OkamotoTeppei Okamoto More articles by this author , Hayato YamamotoHayato Yamamoto More articles by this author , Takahiro YoneyamaTakahiro Yoneyama More articles by this author , Yasuhiro Hashimoto HashimotoYasuhiro Hashimoto Hashimoto More articles by this author , Satoshi SatoSatoshi Sato More articles by this author , and Chikara OhyamaChikara Ohyama More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We aimed to evaluate the effect of apalutamide dose reduction on skin-related adverse events (AEs) and castration-resistant prostate cancer (CRPC)-free survival in patients with advanced prostate cancer (PC). METHODS: We retrospectively evaluated 35 patients with nonmetastatic CRPC and 72 treatment-naïve metastatic castration-sensitive PC (mCSPC) patients treated with apalutamide. The primary outcome was the effect of apalutamide dose reduction on skin AEs. The secondary outcomes were the effect of apalutamide dose reduction on skin AEs in patients with small body size, post-skin AE discontinuation rate, and the effect of apalutamide dose reduction on CRPC-free survival in patients with mCSPC treated with upfront apalutamide plus androgen deprivation therapy. RESULTS: Of the 107 patients, 65 (60.7%) and 42 (39.3%) were treated with full and reduced doses of apalutamide, respectively. The skin AE rate was not significantly different between the groups (55% vs. 43%, p=0.761). The incidence rate of skin AEs in the reduced dose of apalutamide was significantly lower in patients with small body size (body weight <67 kg and body mass index <24 kg/m2) than in those with other body sizes. The apalutamide discontinuation rate after skin AEs significantly differed between the full dose (50%) and reduced dose (16.7%) groups. Of the 72 patients with mCSPC, the CRPC-free survival was not significantly different between the full dose and reduced dose groups. CONCLUSIONS: Apalutamide dose reduction was not significantly associated with the incidence of skin AEs. However, dose reduction for patients with small body size may alleviate skin AEs without sacrificing oncological outcome. Source of Funding: nothing © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e130 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyo Togashi More articles by this author Mutsu, Japan Shingo Hatakeyama More articles by this author Ryuji Tabata More articles by this author Daiji Fujimori More articles by this author Yohei Kawashima More articles by this author Toshikazu Tanaka More articles by this author Teppei Okamoto More articles by this author Hayato Yamamoto More articles by this author Takahiro Yoneyama More articles by this author Yasuhiro Hashimoto Hashimoto More articles by this author Satoshi Sato More articles by this author Chikara Ohyama More articles by this author Expand All Advertisement PDF downloadLoading ...

MP11-09 SECOND LINE PSMA-TARGETED SALVAGE TREATMENT IN PATIENTS WITH miN1/M1a-b OLIGORECURRENT PCa

You have accessJournal of UrologyCME1 Apr 2023MP11-09 SECOND LINE PSMA-TARGETED SALVAGE TREATMENT IN PATIENTS WITH miN1/M1a-b OLIGORECURRENT PCa Lorenzo Bianchi, Eleonora Balestrazzi, Francesco Ceci, Francesco Costa, Matteo Droghetti, Alessandro Pissavini, Pietro Piazza, Andrea Farolfi, Riccardo Mei, Paolo Castellucci, Stefano Puliatti, Giorgio Gandaglia, Alessandro Larcher, Alexandre Mottrie, Alberto Briganti, Alessio Giuseppe Morganti, Stefano Fanti, Francesco Montorsi, Riccardo Schiavina, and Eugenio Brunocilla Lorenzo BianchiLorenzo Bianchi More articles by this author , Eleonora BalestrazziEleonora Balestrazzi More articles by this author , Francesco CeciFrancesco Ceci More articles by this author , Francesco CostaFrancesco Costa More articles by this author , Matteo DroghettiMatteo Droghetti More articles by this author , Alessandro PissaviniAlessandro Pissavini More articles by this author , Pietro PiazzaPietro Piazza More articles by this author , Andrea FarolfiAndrea Farolfi More articles by this author , Riccardo MeiRiccardo Mei More articles by this author , Paolo CastellucciPaolo Castellucci More articles by this author , Stefano PuliattiStefano Puliatti More articles by this author , Giorgio GandagliaGiorgio Gandaglia More articles by this author , Alessandro LarcherAlessandro Larcher More articles by this author , Alexandre MottrieAlexandre Mottrie More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Alessio Giuseppe MorgantiAlessio Giuseppe Morganti More articles by this author , Stefano FantiStefano Fanti More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Riccardo SchiavinaRiccardo Schiavina More articles by this author , and Eugenio BrunocillaEugenio Brunocilla More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PSMA-PET is considered the imaging of choice in patients with recurrent prostate cancer (PCa) after primary treatments. Recurrent PCa includes various clinical settings. Thus, we aimed to explore the oncologic benefit of second-line salvage PSMA-guided MDT (metastases directed treatment) in PCa patients with recurrence after previous salvage treatments and oligo-recurrent N1/M1a-b disease at PSMA-PET. METHODS: We retrospectively analyzed patients underwent RP (radical prostatectomy) for PCa and PSMA-PET (from January 2016 to February 2021) performed for biochemical recurrence (BCR) after first-line salvage therapies for BCR after PR at 3 high volume European Centers. Oligo-recurrent (≤3 lesions) patients with N1/M1a-b disease at PSMA-PET and eligible for MDT were identified. MDT consist of salvage lymph node dissection (sLND) and stereotactic body radiotherapy (SBRT) or combination of both. Conventional approach includes observation or androgen deprivation therapy. Men were stratified according to treatment after PSMA-PET (MDT vs. conventional approach). Kaplan Meier curves were used to assess progression free survival (PFS), metastases free survival (MFS) and CRPC free survival (CRPC-FS) at 3 years of follow up after stratifying according to treatment after PSMA-PET. Multivariable Cox regression was performed to identify independent predictors of progression and metastases. RESULTS: Overall, 113 patients were enrolled: 91 patients were treated with MDT approach and 22 with conventional approach. The median (IQR) follow-up after PSMA-PET was 31 (19-42) months. Overall, no significant differences were found concerning 3-years PFS according to type of treatment (p=0.3). MFS and CRPC-FS estimates at 3 years were 73.5% and 94.7% in patients underwent MDT vs 30.5% and 79.5% in men treated with conventional approach, respectively (all p<0.001). At the multivariable Cox regression analysis, age (HR=0.96) and pT3b-pT4 (HR=2.02) were independent predictors of progression (all p≤0.03), while MDT (HR 0.37) was the only independent predictor of metastases (p= 0.02). CONCLUSIONS: In a selected population of oligo-recurrent N1/M1a-b Pca patients with limited therapeutic chances due to previous salvage treatments, the MDT targeted to PSMA-PET may represent a promising second-line salvage approach to delay further progression to CRPC status. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e126 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lorenzo Bianchi More articles by this author Eleonora Balestrazzi More articles by this author Francesco Ceci More articles by this author Francesco Costa More articles by this author Matteo Droghetti More articles by this author Alessandro Pissavini More articles by this author Pietro Piazza More articles by this author Andrea Farolfi More articles by this author Riccardo Mei More articles by this author Paolo Castellucci More articles by this author Stefano Puliatti More articles by this author Giorgio Gandaglia More articles by this author Alessandro Larcher More articles by this author Alexandre Mottrie More articles by this author Alberto Briganti More articles by this author Alessio Giuseppe Morganti More articles by this author Stefano Fanti More articles by this author Francesco Montorsi More articles by this author Riccardo Schiavina More articles by this author Eugenio Brunocilla More articles by this author Expand All Advertisement PDF downloadLoading ...

MP29-18 ONCOLOGICAL OUTCOMES IN THE METASTATIC LOW TUMOR-BURDEN PROSTATE CANCER ARE NOT SIGNIFICANTLY DIFFERENT FROM THE LOCALLY ADVANCED (T4 OR N1) PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023MP29-18 ONCOLOGICAL OUTCOMES IN THE METASTATIC LOW TUMOR-BURDEN PROSTATE CANCER ARE NOT SIGNIFICANTLY DIFFERENT FROM THE LOCALLY ADVANCED (T4 OR N1) PROSTATE CANCER Toshikazu Tanaka, Shingo Hatakeyama, Ryuji Tabata, Fujita Naoki, Noro Daisuke, Itsuto Hamano, Takahiro Yoneyama, Yasuhiro Hashimoto, Satoshi Sato, Shintaro Narita, Tomonori Habuchi, and Chikara Ohyama Toshikazu TanakaToshikazu Tanaka More articles by this author , Shingo HatakeyamaShingo Hatakeyama More articles by this author , Ryuji TabataRyuji Tabata More articles by this author , Fujita NaokiFujita Naoki More articles by this author , Noro DaisukeNoro Daisuke More articles by this author , Itsuto HamanoItsuto Hamano More articles by this author , Takahiro YoneyamaTakahiro Yoneyama More articles by this author , Yasuhiro HashimotoYasuhiro Hashimoto More articles by this author , Satoshi SatoSatoshi Sato More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Tomonori HabuchiTomonori Habuchi More articles by this author , and Chikara OhyamaChikara Ohyama More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The difference in oncological outcomes between patients with locally advanced (T4 or N+) prostate cancer and metastatic prostate cancer with low tumor-burden disease remain unclear. We retrospectively compared the oncological outcomes between the locally advanced disease (M0-advanced group) and metastatic low-burden disease (M1-low group). METHODS: We evaluated 186 and 319 patients with the M0-advanced and M1-low groups treated with androgen deprivation therapy alone. Castration-resistant prostate cancer (CRPC)-free survival and overall survival were compared by a multivariable Cox regression analysis using inverse probability of treatment weighting method. We also evaluated risk factors for poor prognosis. RESULTS: Of 505, 138 (27.3%) patients underwent local interventions (surgery or radiotherapy). We observed no significant difference in CRPC-free survival and overall survival between the M0-advanced and M1-low groups. Multivariable Cox regression analysis showed that a Gleason score 9-10, T4 or N1 status, and no local intervention were significantly associated with poor prognosis. Local interventions are background difference for local intervention between the groups. CONCLUSIONS: Oncological outcomes of the group M1-low group were not significantly different from the M0-advanced. Gleason score, locally advanced status (T4 or N1), and local intervention potentially associate with oncological outcomes. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e389 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Toshikazu Tanaka More articles by this author Shingo Hatakeyama More articles by this author Ryuji Tabata More articles by this author Fujita Naoki More articles by this author Noro Daisuke More articles by this author Itsuto Hamano More articles by this author Takahiro Yoneyama More articles by this author Yasuhiro Hashimoto More articles by this author Satoshi Sato More articles by this author Shintaro Narita More articles by this author Tomonori Habuchi More articles by this author Chikara Ohyama More articles by this author Expand All Advertisement PDF downloadLoading ...

Strategy for PSA progression in patients undergoing salvage radiation for biochemical recurrence after radical prostatectomy.

The treatment strategy for prostate-specific antigen (PSA) progression in patients who receive salvage radiation therapy (RT) for biochemical recurrence (BCR) after radical prostatectomy (RP) is salvage androgen deprivation therapy (ADT). However, its optimal timing is highly controversial. The study sample consisted of 77 men who underwent RP, received salvage RT against BCR, and underwent salvage ADT for PSA progression. The endpoint of this study was development to castration-resistant prostate cancer (CRPC), from the start of salvage RT. Themedian follow-uptime was 9.5years, and 20 patients experienced CRPC. The multivariable analysis identified PSA-doubling time (PSA-DT) ≤ 12months (hazard ratio, 3.5) and seminal vesicle invasion (SVI) (hazard ratio, 4.4) as independent risk factors. We defined the high-risk and low-risk groups as those with one or two risk factors and no risk factors, respectively. In the high-risk group, a significant difference in time to CRPC was observed between patients who received salvage ADT at PSA ≤ 1.0ng/mL (n = 8) and at > 1.0ng/mL (n = 27) (10-year non-CRPC rate: 100.0% vs. 46.3%, respectively). In contrast, in the low-risk group, no significant difference in CRPC-free survival was observed between patients who received salvage ADT at PSA ≤ 1.0ng/mL (n = 14) and at > 1.0ng/mL (n = 28) (10-year non-CRPC rate: 86.4% vs. 80.8%, respectively). In high-risk patients (PSA-DT ≤ 12months and/or SVI), salvage ADT for PSA progression after salvage RT should be started before the PSA levels exceed 1.0ng/mL.

Comparison of neoadjuvant chemohormonal therapy vs. extended pelvic lymph-node dissection in high-risk prostate cancer treated with robot-assisted radical prostatectomy

We compared the impact of treatment strategies on postoperative complications and prognosis between robot-assisted radical prostatectomy (RARP) plus extended pelvic lymph-node dissection (ePLND) and RARP plus neoadjuvant chemohormonal therapy (NCHT) without ePLND. We retrospectively evaluated 452 patients with high-risk prostate cancer (defined as any one of prostate-specific antigen ≥ 20 ng/mL, Gleason score 8–10, or cT2c–3) who were treated with RARP between January 2012 and February 2021. The patients were divided into two groups: RARP with ePLND (ePLND group) and NCHT plus RARP without ePLND (NCHT group). We compared the complication rate (Clavien–Dindo classification), biochemical recurrence-free survival, and castration-resistant prostate cancer (CRPC)-free survival between the groups. We performed multivariable Cox regression analysis using inverse probability weighting (IPTW) methods to assess the impact of the different treatments on prognosis. There were 150 and 302 patients in the ePLND and NCHT groups, respectively. The postoperative complication rate was significantly higher in the ePLND group than in the NCHT group (P < 0.001). IPTW-adjusted biochemical recurrence-free survival and CRPC-free survival were significantly higher in the NCHT group than in the ePLND group (hazard ratio [HR] 0.29, P < 0.001, and HR 0.29, P = 0.010, respectively). NCHT plus RARP without ePLND may reduce the risk of postoperative complications compared with ePLND during RARP. The impact of treatment strategies on oncological outcomes needs further studies.

The effect of reduced dose of apalutamide on skin adverse events in advanced prostate cancer: A multicenter retrospective study.

151 Background: We aimed to evaluate the effect of a reduced dose of apalutamide on skin-related adverse events (AEs) and castration-sensitive prostate cancer (CRPC)-free survival in patients with advanced prostate cancer. Methods: We retrospectively evaluated 35 patients with non-metastatic CRPC and 72 treatment naïve metastatic castration-sensitive prostate cancer (mCSPC) who were treated with apalutamide. The primary outcome was the effect of apalutamide dose-reduction on skin AEs. The secondary outcomes included the effect of apalutamide dose-reduction on skin AE in patents with small body size, post-skin AEs discontinuation rate, and the effect of apalutamide dose-reduction on CRPC-free survival in patients with mCSPC treated with upfront apalutamide plus androgen deprivation therapy. Results: Of 107 patients, 65 (60.7%) and 42 (39.3%) patients were treated with full- and reduced-dose of apalutamide, respectively. The skin AEs rate was not significantly different between the groups (55% vs. 43%, P = 0.761). The incident of skin AEs in the reduced dose of apalutamide were significantly lower in patients with small body size (body weight &lt;67kg and body mass index &lt; 24kg/m2) than those in other body sizes. Apalutamide discontinuation rate after skin AEs was significantly different between the full-dose (50%) and reduced-dose (16.7%) groups. Of 72 patients with mCSPC, the CRPC-free survival was not significantly different between the full- and reduced-dose groups. Conclusions: A reduced dose of apalutamide was not significantly associated with the incident of skin AEs. However, dose reduction for patients with small body size may decrease skin AEs without sacrificing oncological outcome.

Trends in the use of local intervention and its impact on oncological outcomes for metastatic castration-sensitive prostate cancer: A multicenter retrospective study.

354 Background: The role of local intervention in addition to the standard of care for metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Therefore, this study evaluated the trends of local intervention and their impact on oncological outcomes in patients with mCSPC in real-world practice. Methods: This multicenter retrospective study included 760 patients treated with either androgen deprivation therapy (ADT) without local treatment (no castration-resistant prostate cancer [CRPC] progression within 12 months, control group) or ADT plus local intervention (intervention group) between January 2005 and March 2022. The primary outcome was trends in the use of local intervention in patients with mCSPC. The secondary outcomes included evaluations of factors associated with CRPC-free survival in the intervention group. Results: The use of local intervention gradually increased in combination with upfront treatment for the duration of our study. The number of patients with local intervention combined with upfront treatment was significantly higher in patients with high tumor burden disease than in those with low tumor burden disease. Of the 108 patients who received local intervention comprising radiation therapy targeted to the prostate, a duration of &gt;7 months of initial therapy before local intervention and a level of prostate-specific antigen &lt;0.20 ng/mL at the time of local intervention were significantly associated with prolonged CRPC-free survival. Conclusions: Regardless of the tumor burden, the use of local intervention in combination with upfront therapy to treat mCSPC increased for the duration of our study. Local intervention in addition to the standard of care for mCSPC may be a feasible treatment option for selected patients, taking into consideration the duration of and response to initial treatment.

SOX9 and HMGB3 co-operatively transactivate NANOG and promote prostate cancer progression.

The homeodomain-containing transcription factor NANOG is overexpressed in prostate adenocarcinoma (PCa) and predicts poor prognosis. The SOX family transcription factor SOX9, as well as the transcription co-activator HMGB3 of the HMGB family, are also overexpressed and may play pivotal roles in PCa. However, it is unknown whether SOX9 and HMGB3 interact with each other, or if they regulate NANOG gene transcription. We identified potential SOX9 responsive elements in NANOG promoter, and investigated if SOX9 regulated NANOG transcription in co-operation with HMGB3 by experimental analysis of potential SOX9 binding sites in NANOG promoter, reporter gene transcription assays with or without interference or artificial overexpression of SOX9 and/or HMGB3, and protein-binding assays of SOX9-HMGB3 interaction. Clinicopathologic and prognostic significance of SOX9-HMGB3 overexpression in PCa was analyzed. SOX9 activated NANOG gene transcription by preferentially binding to a highly conserved consensus cis-regulatory element (-573 to -568) in NANOG promoter, and promoted the expression of NANOG downstream oncogenic genes. Importantly, HMGB3 functioned as a partner of SOX9 to co-operatively enhance transactivation of NANOG by interacting with SOX9, predominantly via the HMG Box A domain of HMGB3. Overexpression of SOX9 and/or HMGB3 enhanced PCa cell survival and cell migration and were significantly associated with PCa progression. Notably, Cox proportional regression analysis showed that co-overexpression of both SOX9 and HMGB3 was an independent unfavorable prognosticator for both CRPC-free survival (relative risk [RR] = 3.779，95% confidence interval [CI]: 1.159-12.322, p = 0.028) and overall survival (RR = 3.615，95% CI: 1.101-11.876, p = 0.034). These findings showed a novel SOX9/HMGB3/NANOG regulatory mechanism, deregulation of which played important roles in PCa progression.

Adjuvant radiotherapy in patients with node-positive prostate cancer after radical prostatectomy.

Our study was to determine whether immediate androgen deprivation therapy (ADT) plus radiotherapy (RT) extends survival in men with node-positive prostate cancer (PCa) after radical prostatectomy (RP) compared with those who received ADT alone. A total of 99 consecutive patients with pathological positive lymph nodes (pN1) PCa were included in this study to receive immediate ADT plus RT (n = 70) or to receive immediate ADT alone (n = 29). The primary endpoint was castration-resistant prostate cancer (CRPC) free survival; the secondary endpoints were distant metastasis-free survival. Cox regression was used to assess the independent risk factors for CRPC. The median follow-up time was 34.0 (24.8, 47.8) months and 34.25 (23.0, 49.0) months, respectively, in the ADT + RT group and ADT-alone group. The 5-year CRPC-free survival rate was 79.5% and 58.3%, respectively, in the ADT + RT group and ADT-alone group (p = 0.308). The 5-year distant metastasis-free survival rate was 71.4% and 38.8, respectively, in the ADT + RT group and ADT-alone group (p = 0.478). Compared with ADT-alone group, we saw a modest, but no significant improvement in CRPC-free survival and distant metastasis-free survival in ADT + RT group. The results of Cox regression showed that positive lymph nodes ≥ 4 was an independent risk factor for CRPC (p = 0.041). We found that immediate ADT plus RT compared to ADT alone did not improve CRPC-free and metastasis-free survival. Multivariate Cox regression analyses also indicated that patients with positive lymph nodes < 4 may benefits from ADT plus RT.