Influence of Tumor Characteristics and Time to Metastatic Disease on Oncological Outcomes in Metachronous Metastatic Prostate Cancer Patients.

INTRODUCTION: Metachronous metastatic prostate cancer (mmPCa) patients harbor different characteristics and outcomes, relative to DeNovo metastatic PCa patients. Onset of metastatic disease might be influenced by primary PCa characteristics such as Gleason score (GS) or cancer stage, as well as overall survival (OS) by timing of metastatic onset. PATIENTS AND METHODS: We relied on an institutional tertiary-care database to identify mmPCa patients. Kaplan Meier and Cox Regression models tested for onset of metastases and OS, stratified according to GS, pathological stage and time to mmPCa. RESULTS: Of 341 mmPCa patients, 8% harbored GS6 versus 41% versus 51% GS7 and GS8-10. Median time to onset of metastatic disease was 79 versus 54 versus 41 months for GS6 versus GS7 versus GS8-10 (P = .01). Moreover, median time to onset of metastases was 64 versus 44 months for pT1-2 versus pT3-4 mmPCa patients undergoing radical prostatectomy (P = .027). In multivariable Cox regression models, higher GS and pT-stage was associated with earlier onset of metastases. Additionally, significant OS differences could be observed for time interval of < 24 versus 24-60 versus 60-120 versus ≥ 120 months between primary PCa diagnosis and onset of mmPCa. Specifically, median OS was 56 versus 69 versus 97 months versus not reached (P < .01) for these categories. In multivariable Cox regression, shorter time to metastatic onset was associated with shorter OS. CONCLUSION: Timing of mmPCa is strongly influenced by grading and pT-stage in real-life setting. OS benefits can be observed with longer time interval between primary PCa diagnosis and onset of mmPCa.

Impact of time to metastatic disease onset and extent of disease volume across metastatic hormone-sensitive and castration-resistant prostate cancer.

OBJECTIVE: In recently published phase III trials, overall survival (OS) differences were demonstrated in patients with secondary vs. De Novo and low vs. high volume metastatic hormone-sensitive prostate cancer (mHSPC). We hypothesized that these factors may also be attributable in real-world setting of new intensified combination therapies and in metastatic castration resistant prostate cancer (mCRPC) patients. MATERIALS AND METHODS: We relied on an institutional tertiary-care database to identify mHSPC and subsequent mCRPC patients. The main outcome consisted of time to mCRPC and OS. Patients were stratified according to De Novo vs. secondary and low vs. high volume mHSPC and mCRPC, respectively. RESULTS: Of 504 mHSPC patients, 371 (73.6%) were De Novo vs. 133 (26.4%) secondary mHSPC. Patients with De Novo and high volume mHSPC harbored shorter time to mCRPC and OS than secondary and low volume mHSPC patients (both P < 0.01). After stratification regarding disease volume, median time to mCRPC differed significantly between De Novo high volume (DNHV) vs. De Novo low volume (DNLV) vs. secondary high volume (SecHV) vs. secondary low volume mHSPC patients (SecLV, P < 0.001). Similarly in OS analyses, median OS was 44 vs. 53 vs. 88 vs. 120 months for respectively DNHV vs. SecHV vs. SecLV vs. DNLV mHSPC (P < 0.001). After progression to mCRPC, the effect of onset of metastatic disease and metastatic volume was still observed (all P < 0.01). CONCLUSION: Patients with DNHV mHSPC harbor worse prognosis in a real world setting and in the light of combination therapies. This effect is also discernible in the context of mCRPC.

Impact of homologous recombination repair/BReast CAncer (BRCA) gene alterations on survival in a real-world setting of metastatic prostate cancer.

OBJECTIVE: To investigate alterations of homologous recombination repair (HRR) and especially BReast CAncer 1/2 (BRCA1/2) gene on overall survival (OS). Moreover, to explore the effect of inhibition of poly(ADP-ribose)-polymerase (PARPi) as systemic therapy for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Of all HRR-screened patients with metastatic prostate cancer, baseline characteristics were sampled. Kaplan-Meier estimates and multivariable Cox regression models predicted the effect of HRR/BRCA1/2 alterations on OS. RESULTS: Of 196 eligible patients, 61 (31%) harboured any HRR and 40 (20%) BRCA1/2 alterations. Of HRR alterations, 40 (66%) vs six (10%) vs five (8.2%) vs four (6.6%) vs two (3.3%) vs four (6.6%) were BRCA1/2 vs Ataxia-telangiectasia mutated kinase (ATM) vs checkpoint kinase 2 (CHEK2) vs cyclin-dependent kinase 12 (CDK12) vs Fanconi anaemia complementation Group A (FANCA) vs positive for other mutations. Of these, 30% received a PARPi. OS differed significantly between HRR-positive vs -negative patients. Specifically in hormone-sensitive prostate cancer, the median OS was 63 (HRR positive) vs 57 (BRCA1/2 positive) vs 113 months (HRR negative) (P ≤ 0.01). In mCRPC, OS was 42 (HRR positive) vs 41 (BRCA1/2 positive) vs 70 months (HRR negative) (P ≤ 0.01). HRR and BRCA1/2 alterations were associated with worse OS after multivariable adjustment. Finally, patients with mCRPC with BRCA1/2 mutation treated without PARPi harboured worse OS than patients with BRCA1/2 mutation and PARPi therapy (median OS: 33 vs 48 months, P < 0.03). CONCLUSION: Incidence of HRR alteration in a clinical real-world setting is high when using blood- and tissue-based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA-positive patients with mCRPC with and without PARPi usage vs HRR/BRCA-negative patients.

Contemporary Treatment Patterns and Oncological Outcomes of Metastatic Hormone-sensitive Prostate Cancer and First- to Sixth- line Metastatic Castration-resistant Prostate Cancer Patients.

Background and objective: With approval of novel systemic therapies within the past decade for metastatic hormone-sensitive (mHSPC) and castration-resistant (mCRPC) prostate cancer, patients may receive several therapy lines. However, the use of these treatments is under an ongoing change. We investigated contemporary treatment trends and progression-free (PFS) and overall (OS) survival of different therapy lines. Methods: Relying on our institutional tertiary-care database, we identified mHSPC and mCRPC patients. The main outcome consisted of treatment changes (estimated annual percentage change [EAPC]) within the past decade, as well as PFS and OS for different mHSPC and mCRPC treatment lines. Key findings and limitations: In 1098 metastatic patients, the median age was 70 yr with a median of two systemic therapy lines. For first-line mCRPC between 2013 and 2023, androgen deprivation monotherapy (ADT) monotherapy usage decreased significantly from 31% to 0% (EAPC -38.3%, p < 0.001), while the administration of chemotherapy increased from 16.7% to 33.3% (EAPC: +10.1%, p < 0.001). The PFS/OS rates of mHSPC patients was 21/67 mo, and those for first-, second-, third-, fourth-, fifth-, and sixth-line mCRPC patients were 11/47, eight of 30, seven of 24, six of 19, seven of 17, and seven of 13 mo, respectively. With an increased number of new combination therapy lines received, the median OS in mCRPC improved from 26 mo (one systemic treatment) to 52 mo (two or more lines of systemic treatment). Conclusions and clinical implications: Significant changes in treatment patterns could be observed for mHSPC and mCRPC patients within the past decade, and usage of ADT monotherapy has decreased rapidly in real-world practice. Moreover, PFS decreases significantly with every therapy line, and OS increases with the implementation of new therapies. Patient summary: Improvements in the real-world setting regarding the usage of combination therapies for metastatic hormone-sensitive and castration-resistant prostate cancer were made, which is reflected in contemporary survival outcomes.

Survival of patients with lymph node versus bone versus visceral metastases according to CHAARTED/LATITUDE criteria in the era of intensified combination therapies for metastatic hormone-sensitive prostate cancer.

BACKGROUND: The first approvals of novel systemic therapies within recent years for metastatic hormone-sensitive (mHSPC) were mainly based on improved overall survival (OS) and time to castration resistance (ttCRPC) in mHSPC patients stratified according to CHAARTED low (LV) versus high volume (HV) and LATITUDE low (LR) versus high-risk (HR) disease. METHODS: Relying on our institutional tertiary-care database we identified all mHSPC stratified according to CHAARTED LV versus HV, LATITUDE LR versus HR and the location of the metastatic spread (lymph nodes (M1a) versus bone (M1b) versus visceral/others (M1c) metastases. OS and ttCRPC analyses, as well as Cox regression models were performed according to different metastatic categories. RESULTS: Of 451 mHSPC, 14% versus 27% versus 48% versus 12% were classified as M1a LV versus M1b LV versus M1b HV versus M1c HV with significant differences in median OS: 95 versus 64 versus 50 versus 46 months (p < 0.001). In multivariable Cox regression models HV M1b (Hazard Ratio: 2.4, p = 0.03) and HV M1c (Hazard Ratio: 3.3, p < 0.01) harbored significant worse than M1a LV mHSPC. After stratification according to LATITUDE criteria, also significant differences between M1a LR versus M1b LR versus M1b HR versus M1c HR mHSPC patients were observed (p < 0.01) with M1b HR (Hazard Ratio: 2.7, p = 0.03) and M1c HR (Hazard Ratio: 3.5, p < 0.01), as predictor for worse OS. In comparison between HV M1b and HV M1c, as well as HR M1b versus HR M1c no differences in ttCRPC or OS were observed. CONCLUSIONS: Significant differences exist between different metastatic patterns of HV and LV and HR and LR criteria. Best prognosis is observed within M1a LV and LR mHSPC patients.

Treatment patterns and oncological outcomes of older adults with metastatic prostate cancer in real-world setting.

BACKGROUND: The landscape of systemic therapies for metastatic hormone-sensitive (mHSPC) and castration resistant prostate cancer (mCRPC) extensively improved within the last decades resulting in a significantly prolonged overall survival. However, subgroup analyses of phase III trials suggest potentially different overall survival outcomes for older adults. METHODS: We relied on our institutional metastatic prostate cancer database to identify mHSPC and subsequently mCRPC patients. Older adults were stratified according to age groups 70-74 versus ≥75-79 versus ≥80 years at metastatic occurrence. Subsequently, uni- and multivariable time to mCRPC and overall survival analyses were performed. RESULTS: Of 494 older adults, 217 (44%) were 70-74 versus 180 (36%) 75-79 versus 97 (20%) ≥80 years old. Rates of local prostate cancer treatment differed significantly between all three groups (p < 0.01). Regarding mHSPC treatment, androgen receptor signaling inhibitors (ARSI) were administered in 30-39% of patients and docetaxel with 9% in age group 70-74 years and 6% and 3% in age groups 75-79 years and ≥80 years. Regarding mCRPC treatment, significant differences between treatment proportions were observed (p < 0.01). Most common treatment was ARSI for all three groups. Conversely, chemotherapy was more frequently administered in patients aged 70-74 (16%), relative to 4% and 3% in 75-79 year and ≥80 year aged patients. In univariable and multivariable time to mCRPC analyses, overall survival in mHSPC and OS in mCRPC analyses, no significant differences between all three age groups were observed (all p ≥ 0.3). CONCLUSIONS: Treatment patterns differ significantly between older adults with metastatic prostate cancer. However, these differences may not result in differences of overall life expectancy.

Nerve-sparing radical prostatectomy using the neurovascular structure-adjacent frozen-section examination (NeuroSAFE): results after 20 years of experience.

OBJECTIVES: To evaluate the long-term oncological outcomes and functional results of the neurovascular structure-adjacent frozen-section examination (NeuroSAFE) during nerve-sparing (NS) radical prostatectomy (RP). MATERIALS AND METHODS: A 10-yr survival analysis on 11069 RPs performed with or without the NeuroSAFE, between January 2002 to June 2011 was carried out. In the NeuroSAFE cohort, the neurovascular structure-adjacent prostatic margins are removed and stained for cryo-sectioning during RP. In case of a PSM, partial or full removal of the neurovascular bundle was performed. The impact of NeuroSAFE on biochemical recurrence-free survival (BFS), salvage radiation therapy-free survival, metastasis-free survival, and prostate cancer-specific survival at 10 years was analyzed. 1-year (1-yr) erectile function (EF), 1-yr, and 2-yr continence rates were assessed in propensity score-based matched cohorts. RESULTS: Median follow-up was 121 (IQR: 73, 156) months. No differences in BFS between NeuroSAFE and non-NeuroSAFE were recorded (10-yr BFS: NeuroSAFE vs non-Neurosafe, pT2: 81% vs 84%, p = 0.06; pT3a: 58% vs. 63%, p = 0.6; ≥pT3b: 22% vs. 27%, p = 0.99). No differences were found between the two groups in terms of sRFS (pT2: p = 0.1; pT3a: p = 0.4; ≥pT3b: p = 0.4) (Fig. 1B, Table 2), and MTS (pT2: p = 0.3; pT3a: p = 0.6; ≥pT3b: p = 0.9). The NeuroSAFE-navigated patients reported a better 1-yr EF than non-NeuroSAFE (68% vs. 58%, p = 0.02) and no differences in 1-yr and 2-yr continence rates (92.4% vs. 91.8%, and 93.4% vs. 93%, respectively). The main limitation is the retrospective study design. CONCLUSIONS: While the NeuroSAFE approach did not show significant improvements in long-term oncologic or continence outcomes, it did provide an opportunity for a higher proportion of patients to improve postoperative functional results, possibly through increased nerve-sparing procedures.

Impact of COVID-19 on the time to counseling and treatment of prostate cancer.

PURPOSE: This study investigates how the COVID-19 pandemic (CP) impacted the timeline between initial diagnosis (ID) of prostate carcinoma and subsequent therapy consultation (TC) or radical prostatectomy (RP) due to the implementation of a "minimal contact concept," which postponed clinical examinations until the day of admission. METHODS: We analyzed patient data from a tertiary care center from 2018 to September 2021. The focus was on comparing the time intervals from ID to TC and from ID to RP before and during the CP. RESULTS: Of 12,255 patients, 6,073 (61.6%) were treated before and 3,791 (38.4%) during the CP. The median time from ID to TC reduced from 37 days (IQR: 21 - 58d) pre-CP to 32 days (IQR: 20 - 50d) during CP (p < 0.001). Similarly, the time from ID to RP decreased from 98 days (IQR: 70 - 141d) to 75 days (IQR: 55 - 108d; p < 0.001) during the CP. There was a significant decrease in low-risk tumor cases at ID (18.9% vs. 21.4%; p = 0.003) and post-RP (4% vs. 6.7%; p < 0.001) during the CP. CONCLUSION: Our findings suggest that the COVID-19 pandemic facilitated more timely treatment of prostate cancer, suggesting potential benefits for both low-risk and aggressive tumor management through expedited clinical procedures.

Biochemical Response of <0.1 ng/ml Predicts Therapy-free Survival of Prostate Cancer Patients following Prostate-specific Membrane Antigen-targeted Salvage Surgery.

BACKGROUND: In a subset of patients with oligorecurrent prostate cancer (PCa), salvage surgery with prostate-specific membrane antigen (PSMA) radioguided surgery (PSMA-RGS) seems to be of value. OBJECTIVE: To evaluate whether a lower level of postoperative prostate-specific antigen (PSA; <0.1 ng/ml) is predictive of therapy-free survival (TFS) following salvage PSMA-RGS. DESIGN, SETTING, AND PARTICIPANTS: This cohort study evaluated patients with biochemical recurrence after radical prostatectomy and oligorecurrent PCa on PSMA positron emission tomography treated with PSMA-RGS in three tertiary care centers (2014-2022). INTERVENTION: PSMA-RGS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Postsalvage surgery PSA response was categorized as <0.1, 0.1-<0.2, or >0.2 ng/ml. Kaplan-Meier and multivariable Cox regression models evaluated TFS according to PSA response. RESULTS AND LIMITATIONS: Among 553 patients assessed, 522 (94%) had metastatic soft tissue lesions removed during PSMA-RGS. At 2-16 wk after PSMA-RGS, 192, 62, and 190 patients achieved PSA levels of <0.1, 0.1-<0.2, and >0.2 ng/ml, respectively. At 2 yr of follow-up, TFS rate was 81.1% versus 56.1% versus 43.1% (p < 0.001) for patients with PSA <0.1 versus 0.1-<0.2 versus >0.2 ng/ml. In multivariable analyses, PSA levels of 0.1-0.2 ng/ml (hazard ratio [HR]: 1.9, confidence interval [CI]: 1.1-3.1) and ≥0.2 ng/ml (HR: 3.2, CI: 2.2-4.6, p < 0.001) independently predicted the need for additional therapy after PSMA-RGS. The main limitation is the lack of a control group. CONCLUSIONS: For patients after salvage PSMA-RGS, a lower biochemical response (PSA <0.1 ng/ml) seems to predict longer TFS. This insight may help in counseling patients postoperatively as well as guiding the timely selection of additional therapy. PATIENT SUMMARY: We studied what happened to prostate cancer patients in three European centers who had salvage surgery using a special method called prostate-specific membrane antigen-targeted radioguidance. We found that patients who had low prostate-specific antigen levels soon after surgery were less likely to need further treatment for a longer time.

Impact of PSA nadir, PSA response and time to PSA nadir on overall survival in real-world setting of metastatic hormone-sensitive prostate cancer patients.

BACKGROUND: To evaluate the impact of prostate-specific antigen (PSA) nadir, PSA response and time to PSA nadir (TTN) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies. METHODS: Different PSA nadir cut-offs (including ultra-low PSA) were tested for OS analyses. Additionally, PSA response ≥99% was evaluated, as well as TTN categorized as <3 versus 3-6 versus 6-12 versus >12 months. Multivariable Cox regression models predicted the value of PSA nadir cut-offs, PSA response and TTN on OS. Sensitivity analyses were performed in de novo and high volume mHSPC patients. RESULTS: Of 238 eligible patients, PSA cut-offs of <0.2 versus 0.2-4.0 versus >4.0 ng/mL differed significantly regarding median OS (96 vs. 56 vs. 44 months, p < 0.01), as well as in subgroup analyses of de novo mHSPC patients and multivariable Cox regression models. A more stringent PSA cut-off of <0.02 versus 0.02-0.2 versus >0.2 ng/mL also yielded significant median OS differences (not reached vs. 96 vs. 50 months, p < 0.01), even after additional multivariable adjustment. A PSA response ≥99% was also significantly associated with better OS than counterparty with <99% response, even after multivariable adjustment (both p < 0.02). When TTN groups were compared, patients with longer TTN harbored more extended OS than those with short TTN (<3 vs. 3-6 vs. 6-12 vs. >12 months: 34 vs. 50 vs. 67 vs. 96 months, p < 0.01). Virtually similar results were observed in sensitivity analyses for high volume mHSPC patients. CONCLUSIONS: In times of combination therapies for mHSPC, a PSA nadir of respectively, <0.2 and <0.02 ng/mL are associated with best OS rates. Moreover, a relative PSA response ≥99% and a longer TTN are clinical important proxies for favorable OS estimates.

Robot-assisted vs open retropubic radical prostatectomy: a propensity score-matched comparative analysis based on 15 years and 18,805 patients.

PURPOSE: To compare oncological, functional, and surgical outcomes of a large cohort of patients who underwent open retropubic radical prostatectomy (ORP) or robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: Data from 18,805 RPs performed with either the open or the robot-assisted approaches at a single tertiary referral center between 2008 and 2022 were analyzed. The impact of surgical approach on biochemical recurrence-free survival, salvage radiotherapy-free survival, and metastasis-free survival was analyzed by log-rank test and Kaplan-Meier analysis in a propensity score (PS)-based matched cohort. Intraoperative and postoperative surgical outcomes were assessed. One-week, 3-month, and 12-month continence rates and 12-month erectile function (EF) were analyzed. RESULTS: No statistically significant differences in oncological outcomes were found between ORP and RARP. A slight statistically significant difference in favor of RARP was noted in urinary continence at 3 months (RARP vs. ORP: 81% vs. 77%, p = 0.007) and 12 months (91% vs. 89.3%, p = 0.008), respectively. The rate of EF was statistically significantly higher (60%) after RARP than after ORP (45%, p < 0.001). CONCLUSION: Both RARP and ORP yielded similar oncological outcomes. RARP offered a slight advantage in terms of continence recovery, but its clinical significance may be less meaningful. RARP resulted in significantly improved postoperative EF, suggesting a potential influence of both surgical experience and minimally invasive approach.

Feasibility of Next-generation Sequencing of Liquid Biopsy (Circulating Tumor DNA) Samples and Tumor Tissue from Patients with Metastatic Prostate Cancer in a Real-world Clinical Setting in Germany.

BACKGROUND AND OBJECTIVE: With European Medicines Agency approval of PARP inhibitors in metastatic castration-resistant prostate cancer and ongoing trials in metastatic hormone-sensitive prostate cancer, detection of genetic alterations in BRCA1/2 and other homologous recombination repair genes has gained an important role. Our aim was to investigate the feasibility and comparability of comprehensive next-generation sequencing (NGS) of liquid biopsy (LB; circulating tumor DNA) and tumor tissue (TT) samples in a real-world clinical setting. METHODS: The study cohort consisted of 50 patients with metastatic prostate cancer (mPC) who had TT NGS performed for BRCA1/2 alterations and consent for additional LB NGS. The Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific, Waltham, MA, USA) was used for TT NGS. The Guardant360 83-gene assay (Guardant Health, Palo Alto, CA, USA) was used for LB NGS, including all types of somatic alterations, microsatellite instability, and blood tumor mutational burden. We calculated BRCA1/2 alteration rates and the negative percentage agreement (NPA) and positive percentage agreement (PPA) between TT and LB results. KEY FINDINGS AND LIMITATIONS: TT NGS was successful in 44/50 patients (88%), with pathogenic BRCA1/2 alterations detected in four (9%). LB NGS was successful in all 50 patients (100%), with BRCA1/2 alterations detected in ten (20%). In a subgroup analysis for the 44 patients with successful TT NGS, NPA was 85% and PPA was 50%. The median time between TT sample collection and blood sampling for NGS was 132 wk (IQR 94-186). The limited sample size and differences in the time of NGS assessment are limitations. CONCLUSIONS AND CLINICAL IMPLICATIONS: LB NGS resulted in a higher detection rate for BRCA1/2 alterations in comparison to conventional TT NGS (20% vs 9%). Ideally, BRCA1/2 testing should be based on both approaches to identify all patients with mPC eligible for PARP inhibitor therapy. PATIENT SUMMARY: Our study shows that genetic tests for both tumor tissue and blood samples results in higher rates of detection of BRCA1/2 gene alterations in patients with metastatic prostate cancer.

[Local therapies for oligometastatic hormone-sensitive prostate cancer]. / Stellenwert der lokalen Therapien beim oligometastasierten, hormonsensitiven Prostatakarzinom.

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