TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer

Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of Cell Search-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis. See related commentary by Rebello et al., p. 169

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.The Belgian Foundation Against Cancer (grant number C/2014/227); Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (grant number 00000000116000000206); Royal College of Surgeons/Cancer Research UK (C19198/A1533); The Cancer Research Funds of Radiumhemmet, through the PCM program at KI (grant number 163012); The Erling-Persson family foundation (grant number 4-2689-2016); the Swedish Research Council (grant number K2010-70X-20430-04-3), and the Swedish Cancer Foundation (grant number 09-0677)

Survival outcomes and pattern of relapse after SABR for oligometastatic prostate cancer

INTRODUCTION: The 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. METHODS: This 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. RESULTS: Eighty-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, p18 months), 28% (22/79) of patients wmere oligoprogressive (≤3 new lesions) and 27% (21/79) developed a polymetastatic relapse. CONCLUSION: In 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

Multicentric experience in Retzius-sparing robot-assisted radical prostatectomy performed by expert surgeons for high-risk prostate cancer

BACKGROUND: The study aim was to report the results of Retzius-Sparing robot-assisted radical Prostatectomy (RSP) in high-risk prostate cancer (HR-PCa) patients in a multicentric setting of expert surgeons and to analyze predictors of positive surgical margins (PSMs) and urinary continence recovery. METHODS: We retrospectively evaluated all consecutive HR-PCa patients who underwent RSP by expert surgeons in 7 centers. Pre-, peri-and postoperative features were collected. Minimum surgical experience required was 100 RSP cases. The oncological outcomes evaluated were PSMs and biochemical relapse (BCR). Urinary continence was defined as no pad or safety pad. Erectile function was defined as erections sufficient for intercourse. RESULTS: We collected 579 patients operated by 9 surgeons. Median age was 66, median PSA was 9,6 ng/mL. ISUP biopsy was 1 in 3.8%, 2 in 23%, 3 in 32,6%, 4 in 19,9%, 5 in 20,7; median surgical time was 195 minutes. Pathological stage was pT2 in 40,1%, pT3a in 35,9%, pT3b in 23,1%, and pT4 in 0,9% of cases. PSMs were present in 31,3% of cases. Urinary continence was achieved in 66,8% of cases one week after catheter removal. At 22 months (median follow-up), 89,1% patients were continent, BCR occurred in 27,5% patients. In multivariate analysis, PSA, prostate volume, surgical time were independent predictors of PSMs; ASA score and PSMs predicted urinary continence. CONCLUSIONS: We report the first multicentric experience of RSP for HR-PCa. Considering HR cases as those with the worst functional results, 89% of continent patients confirms that RSP helps achieve good functional results. (Cite this article as: Galfano A, Tappero S, Eden C, Dell'Oglio P, Fransis K, Guo H, et al. Multicentric experience in Retzius-sparing robot-assisted radical prostatectomy performed by expert surgeons for high-risk prostate cancer. Minerva Urol Nephrol 2022;74:607-14. DOI: 10.23736/S2724-6051.22.04857-1

Multicentric prospective local treatment of metastatic prostate cancer (LoMP) study

Objectives To investigate the role of cytoreductive radical prostatectomy in addition to standard of care for patients with newly diagnosed metastatic prostate cancer. Materials and Methods This multicentre, prospective study included asymptomatic patients from 2014 to 2018 (NCT02138721). Cytoreductive radical prostatectomy was offered to all fit patients with resectable tumours, resulting in 40 patients. Standard of care was administered to 40 patients who were ineligible or unwilling to undergo surgery. The primary endpoint was castration resistant cancer-free survival at the time point of ≥50% events. The secondary endpoint was local event-free survival. Kaplan–Meier and Cox regression analyses with propensity-score analysis were applied. Results After a median (quartiles) follow-up of 35 (24–47) months, 42 patients became castration-resistant or died. The median castration resistant cancer-free survival was 53 (95% confidence interval [CI] 14–92) vs 21 (95% CI 15–27) months for cytoreductive radical prostatectomy compared to standard of care (P = 0.017). The 3-year estimates for local event-free survival were 83% (95% CI 71–95) vs 59% (95% CI 51–67) for cytoreductive radical prostatectomy compared to standard of care (P = 0.012). However, treatment group showed no significance in the multivariable models for castration resistant cancer-free survival (P = 0.5) or local event-free survival (P = 0.3), adjusted for propensity-score analysis. Complications were similar to the non-metastatic setting. Patients undergoing surgery were younger, with lower baseline prostate-specific antigen levels, alkaline phosphatase levels and metastatic burden. Conclusion The present LoMP study was unable to show a difference between the two inclusion groups regarding castration resistant cancer-free survival for asymptomatic patients with newly diagnosed metastatic prostate cancer. These results validate previous evidence that, in well-selected and informed patients, cytoreductive radical prostatectomy is feasible and safe, with corresponding continence rates compared to the non-metastatic, high-risk setting. Whether cytoreductive radical prostatectomy could be a valuable option to achieve good local palliation needs to be further researched. Overall, the role of cytoreductive radical prostatectomy needs to be further explored in randomized studies to correct for potential bias