M1a prostate cancer:Results of a Dutch multidisciplinary consensus meeting

ObjectivesTo determine the consensus of a Dutch multidisciplinary expert panel on the diagnostic evaluation and treatment of de novo and recurrent metastatic prostate cancer (PCa) limited to non-regional lymph nodes (M1a) in daily clinical practice.Materials and methodsThe panel consisted of 37 Dutch specialists from disciplines involved in the management of M1a PCa (urology, medical and radiation oncology, radiology, and nuclear medicine). We used a modified Delphi method consisting of two voting rounds and a consensus meeting (video conference). Consensus (good agreement) was defined as the situation in which ≥ 75% of the panelists chose the same option.ResultsConsensus existed for 57% of the items. The panel agreed that prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) is the most appropriate standard imaging modality to identify de novo (100%) and recurrent (97%) M1a PCa. Androgen deprivation therapy (ADT) combined with radiotherapy to the prostate ± the M1a lesion(s) was most frequently considered an option for de novo M1a PCa. For M1a as recurrent disease, ADT alone, deferring treatment, or local radiotherapy to the M1a lesion(s) were judged to be the most important treatment options. However, no specific indications for treatment choice in relation to disease characteristics could be formulated.ConclusionsThe Dutch consensus panel preferred PSMA-PET/CT as the standard diagnostic modality to detect M1a PCa. Although potential treatment options were identified, explicit recommendations could not be formulated. This might (partly) be explained by the absence of high-level clinical evidence in this subset of patients. Further research is, therefore, strongly encouraged

Oligometastatic Prostate Cancer:Results of a Dutch Multidisciplinary Consensus Meeting

Background: Oligometastatic prostate cancer (OMPC) is a heterogeneous disease state that is imperfectly understood, and its clinical implications are unclear. Objective: To determine the consensus of a Dutch multidisciplinary expert panel on biological aspects, treatment goals, and management of OMPC in daily clinical practice. Design, setting, and participants: The study comprised a modified Delphi method including an explorative survey with various statements and questions, followed by a consensus meeting to discuss and determine the agreement with revised statements and related items. The panel consisted of 34 Dutch representatives from urology, medical and radiation oncology, radiology, nuclear medicine, and basic research. Outcome measurements and statistical analysis: Agreement was determined with statements (five-point scale). Consensus was defined as ≥75% panel agreement with a statement. Results and limitations: Consensus existed for 56% of statements. The panel agreed that OMPC comprises a limited metastatic spread in the hormone-sensitive setting, in both the synchronous and the metachronous presentation. Limited metastatic spread was believed to involve three to five metastases and a maximum of two organs. Prostate-specific membrane antigen positron emission tomography/computed tomography scan was currently perceived as the most accurate diagnostic imaging modality. Although there was a consensus that targeted treatment of all metastases in OMPC will delay further dissemination of the disease, opinions on specific treatment regimens were divided. Panel outcomes were limited by the lack of scientific evidence on OMPC. Conclusions: A multidisciplinary panel reached a consensus that OMPC is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should focus on both the biology and the clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC. Patient summary: A group of Dutch medical specialists agreed that prostate cancer patients having few metastases may benefit from a new therapeutic approach. Clinical studies need to determine which treatment is best for each specific situation. A multidisciplinary panel reached consensus that oligometastatic prostate cancer (OMPC) is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should provide insight into the biology and clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC

Treatment Patterns and Use of Immune Checkpoint Inhibitors Among Patients with Metastatic Bladder Cancer in a Dutch Nationwide Cohort

Since 2017, two immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of metastatic urothelial carcinoma in Europe: pembrolizumab as second-line therapy and avelumab as maintenance therapy. Our aim was to describe the use of ICIs as first and later lines of treatment in patients with metastatic bladder cancer (mBC) in the Netherlands. We identified all patients diagnosed with primary mBC between 2018 and 2021 in the Netherlands from the Netherlands Cancer Registry (NCR). NCR data were supplemented with data from the Dutch nationwide Prospective Bladder Cancer Infrastructure (ProBCI) collected from medical files, with follow-up until death or end of data collection on January 1, 2023. A total of 1525 patients were diagnosed with primary mBC between 2018 and 2021 in the Netherlands. Of these, 34.7% received at least one line of systemic treatment with chemotherapy or ICI. After first-line platinum-based chemotherapy, 34.1% received second-line ICI and 3.9% received maintenance ICI. Among patients who completed or discontinued first-line cisplatin- or carboplatin-based chemotherapy after approval of maintenance ICI in the Netherlands, 40.7% and 19.7% received second-line ICI, and 9.3% and 14.1% received maintenance ICI, respectively. ICI use for mBC treatment has not increased considerably since their introduction in 2017. Future research should assess whether the introduction of maintenance avelumab (available since April 2021 in the Netherlands) has led to increases in the proportion of patients with mBC patients receiving systemic treatment and the proportion receiving ICI. Patient summary: We assessed the rate of immunotherapy use for patients with metastatic bladder cancer in the Netherlands. Since its introduction, immunotherapy has been used in a minority of patients, mostly as second-line treatment after platinum-based chemotherapy.</p

RNA:protein ratio of the unicellular organism as a characteristic of phosphorous and nitrogen stoichiometry and of the cellular requirement of ribosomes for protein synthesis

Background Mean phosphorous:nitrogen (P:N) ratios and relationships of P:N ratios with the growth rate of organisms indicate a surprising similarity among and within microbial species, plants, and insect herbivores. To reveal the cellular mechanisms underling this similarity, the macromolecular composition of seven microorganisms and the effect of specific growth rate (SGR) on RNA:protein ratio, the number of ribosomes, and peptide elongation rate (PER) were analyzed under different conditions of exponential growth. Results It was found that P:N ratios calculated from RNA and protein contents in these particular organisms were in the same range as the mean ratios reported for diverse organisms and had similar positive relationships with growth rate, consistent with the growth-rate hypothesis. The efficiency of protein synthesis in microorganisms is estimated as the number of active ribosomes required for the incorporation of one amino acid into the synthesized protein. This parameter is calculated as the SGR:PER ratio. Experimental and theoretical evidence indicated that the requirement of ribosomes for protein synthesis is proportional to the RNA:protein ratio. The constant of proportionality had the same values for all organisms, and was derived mechanistically from the characteristics of the protein-synthesis machinery of the cell (the number of nucleotides per ribosome, the average masses of nucleotides and amino acids, the fraction of ribosomal RNA in the total RNA, and the fraction of active ribosomes). Impairment of the growth conditions decreased the RNA:protein ratio and increased the overall efficiency of protein synthesis in the microorganisms. Conclusion Our results suggest that the decrease in RNA:protein and estimated P:N ratios with decrease in the growth rate of the microorganism is a consequence of an increased overall efficiency of protein synthesis in the cell resulting from activation of the general stress response and increased transcription of cellular maintenance genes at the expense of growth related genes. The strong link between P:N stoichiometry, RNA:protein ratio, ribosomal requirement for protein synthesis, and growth rate of microorganisms indicated by the study could be used to characterize the N and P economy of complex ecosystems such as soils and the oceans

Talazoparib, a Poly(ADP-ribose) Polymerase Inhibitor, for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses

BACKGROUND: The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib. PATIENTS AND METHODS: Men received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs. RESULTS: In the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127]). CONCLUSION: Common TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC. CLINICALTRIALS.GOV IDENTIFIER: NCT0314879

Symptomatic Skeletal Events and the Use of Bone Health Agents in a Real-World Treated Metastatic Castration Resistant Prostate Cancer Population:Results From the CAPRI-Study in the Netherlands

Background: Patients with metastatic castration resistant prostate cancer (mCRPC) are at risk of symptomatic skeletal events (SSE). Bone health agents (BHA, ie bisphosphonates and denosumab) and new life-prolonging drugs (LPDs) can delay SSEs. The aim of this study is to investigate the use of BHAs in relation to SSEs in treated real-world mCRPC population. Patients and Methods: We included patients from the CAPRI registry who were treated with at least one LPD and diagnosed with bone metastases prior to the start of first LPD (LPD1). Outcomes were SSEs (external beam radiation therapy (EBRT) to the bone, orthopedic surgery, pathologic fracture or spinal cord compression) and SSE-free survival (SSE-FS) since LPD1. Results: One-thousand nine hundred and twenty-three patients were included with a median follow-up from LPD1 of 16.7 months. Fifty-two percent (n = 996) started BHA prior or within 4 weeks after the start of LPD1 (early BHA). In total, 41% experienced at least one SSE. SSE incidence rate was 0.29 per patient year for patients without BHA and 0.27 for patients with early BHA. Median SSE-FS from LPD1 was 12.9 months. SSE-FS was longer in patients who started BHA early versus patients without BHA (13.2 vs. 11.0 months, P =.001). Conclusion: In a real-world population we observed an undertreatment with BHAs, although patients with early BHA use had lower incidence rates of SSEs and longer SSE-FS. This finding was irrespective of type of SSE and presence of risk factors. In addition to LPD treatment, timely initiation of BHAs is recommended in bone metastatic CRPC-patients with both pain and/or opioid use and prior SSE

Patients with Biallelic BRCA1/2 Inactivation respond to Olaparib treatment across Histologic tumor types

Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with offlabel olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive offlabel drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay

PSMA-RLT in Patients with Metastatic Hormone-Sensitive Prostate Cancer : A Retrospective Study

Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMARLT in early-stage and hormone-sensitive metastatic prostate cancer patients. Methods: A retrospective study was performed in patients who received 177Lu-PSMA and/or 225Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. Results: In total, 20 patients were included of which 18 patients received 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1–6) and a median activity of 6.2 GBq 177Lu-PSMA per cycle (interquartile range (IQR) 5.2–7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1–2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received 225Ac-PSMA developed grade 3–4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09–19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. Conclusions: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up

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