Role of Local and/or Metastasis-directed Therapy in Patients with Hormone-sensitive M1a Prostate Cancer:A Systematic Review

CONTEXT: It remains unclear whether men with hormone-sensitive prostate cancer (PCa) metastasized to nonregional lymph nodes (M1a) benefit from prostate-directed therapy (PDT) and/or metastasis-directed therapy (MDT). OBJECTIVE: To systematically summarize the literature regarding oncological outcomes of de novo and recurrent M1a PCa patients treated with PDT and/or MDT. EVIDENCE ACQUISITION: We searched Medline (Ovid), Embase, and Scopus according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for reports on oncological outcomes of de novo or recurrent hormone-sensitive M1a PCa patients treated with PDT (radical prostatectomy or radiotherapy) and/or MDT (nodal radiotherapy or salvage lymph node dissection) with or without androgen deprivation therapy. A descriptive data synthesis and a methodological quality assessment were performed to evaluate the impact of PDT and/or MDT on survival in M1a PCa patients. EVIDENCE SYNTHESIS: A total of 6136 articles were screened and 24 studies were included in this systematic review. In de novo M1a PCa patients, PDT was associated with improved oncological outcomes compared with no PDT. In recurrent M1a PCa, MDT could delay the need for systemic treatment in a selection of patients, but high-level evidence from prospective phase III randomized controlled trials is still awaited. CONCLUSIONS: This systematic review summarized the limited literature data on the management of M1a PCa. Subgroup analyses suggest a role for PDT plus systemic therapy in de novo M1a PCa. MDT to distant nodal metastases delayed the need for systemic therapy in recurrent disease, but robust data are lacking. The predominantly retrospective nature of the included studies and significant heterogeneity in study designs limit the strength of evidence. PATIENT SUMMARY: We reviewed the treatment of patients with prostate cancer that has spread to lymph nodes outside the pelvis without metastases in other organ systems. There is evidence that treatment of the primary prostate tumor improves outcomes in well-selected patients and that treatment targeting distant lymph node metastases can delay the start of systemic treatment.</p

Third-line Life-prolonging Drug Treatment in a Real-world Metastatic Castration-resistant Prostate Cancer Population:Results from the Dutch Castration-resistant Prostate Cancer Registry

Third-line life-prolonging drugs (LPDs) might not be appropriate for all metastatic castration-resistant prostate cancer patients. We developed a prognostic model and identified a high-risk subgroup in which no meaningful benefit from third-line LPDs is derived in clinical practice

Being Transparent About Brilliant Failures:An Attempt to Use Real-World Data in a Disease Model for Patients with Castration-Resistant Prostate Cancer

Background: Real-world disease models spanning multiple treatment lines can provide insight into the (cost) effectiveness of treatment sequences in clinical practice. Objective: Our objective was to explore whether a disease model based solely on real-world data (RWD) could be used to estimate the effectiveness of treatments for patients with castration-resistant prostate cancer (CRPC) that could then be suitably used in a cost-effectiveness analysis. Methods: We developed a patient-level simulation model using patient-level data from the Dutch CAPRI registry as input parameters. Time to event (TTE) and overall survival (OS) were estimated with multivariate regression models, and type of event (i.e., next treatment or death) was estimated with multivariate logistic regression models. To test internal validity, TTE and OS from the simulation model were compared with the observed outcomes in the registry. Results: Although patient characteristics and survival outcomes of the simulated data were comparable to those in the observed data (median OS 20.6 vs. 19.8 months, respectively), the disease model was less accurate in estimating differences between treatments (median OS simulated vs. observed population: 18.6 vs. 17.9 [abiraterone acetate plus prednisone], 24.0 vs. 25.0 [enzalutamide], 20.2 vs. 18.7 [docetaxel], and 20.0 vs. 23.8 months [radium-223]). Conclusions: Overall, the disease model accurately approximated the observed data in the total CRPC population. However, the disease model was unable to predict differences in survival between treatments due to unobserved differences. Therefore, the model is not suitable for cost-effectiveness analysis of CRPC treatment. Using a combination of RWD and data from randomised controlled trials to estimate treatment effectiveness may improve the model

Lutetium-177-PSMA-I&amp;T as metastases directed therapy in oligometastatic hormone sensitive prostate cancer, a randomized controlled trial

Background: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177Lu-PSMA-I&T in a randomized multicenter setting. Methods & design: This study compares 177Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression. Discussion: This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177Lu-PSMA-I&T for patients with oHSPC. Trial registration: Clinicaltrials.gov identifier: NCT04443062

Update to a randomized controlled trial of lutetium-177-PSMA in Oligo-metastatic hormone-sensitive prostate cancer:the BULLSEYE trial

Background: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. Changes in methods and materials: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; “Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer” and is now partly supported by Advanced Accelerator Applications, a Novartis Company. Conclusions: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced. Trial registration: ClinicalTrials.gov NCT04443062. First posted: June 23, 2020

Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.

Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity