Until recently, the treatment of metastatic castration-resistant prostate cancer (mCRPC) relied exclusively on hormonal therapies and taxane chemotherapy. The advent of modern molecular profiling methods applied in the clinic, namely, next-generation sequencing and advanced positron emission tomography (PET) imaging, has allowed for the development of biomarker-driven therapeutics including anti-PD-L1 therapy for microsatellite instability-high or tumor mutation burden-high disease, poly(ADP-ribose) polymerase (PARP) inhibitors for patients with DNA damage repair mutations, and lutetium 177 vipivotide tetraxetan (177Lu-PSMA-617) for patients with prostate-specific membrane antigen (PSMA) PET-avid disease. While these targeted therapies have improved outcomes, there is an opportunity to refine biomarkers to optimize patient selection, understand resistance, and develop novel combination strategies. In addition, studies in the laboratory and in patient-derived samples have shown that a subset of mCRPC tumors lose expression of common prostate cancer markers such as prostate-specific antigen and PSMA because of lineage plasticity and the development of non-androgen receptor (AR)-driven disease. Non-AR-driven prostate cancer has been associated with aggressive behavior and poor prognosis, including in some cases histologic transformation to a poorly differentiated neuroendocrine prostate cancer (NEPC). The clinical management of NEPC typically follows the treatment paradigm for small cell lung cancer and increasingly relies on genomic and phenotypic characterization of disease, including loss of tumor suppressors and expression of cell surface markers such as DLL3. Therefore, both genomic subtyping and phenotypic subtyping are important to consider and can guide the clinical management of patients with advanced prostate cancer.

The application of multi‑omics methodologies, encompassing genomics, transcriptomics, proteomics, metabolomics and integrative genomics, has markedly enhanced the understanding of prostate cancer (PCa). These methods have facilitated the identification of molecular pathways and biomarkers crucial for the early detection, prognostic evaluation and personalized treatment of PCa. Studies using multi‑omics technologies have elucidated how alterations in gene expression and protein interactions contribute to PCa progression and treatment resistance. Furthermore, the integration of multi‑omics data has been used in the identification of novel therapeutic targets and the development of innovative treatment modalities, such as precision medicine. The evolving landscape of multi‑omics research holds promise for not only deepening the understanding of PCa biology but also for fostering the development of more effective and tailored therapeutic interventions, ultimately improving patient outcomes. The present review aims to synthesize current findings from multi‑omics studies associated with PCa and to assess their implications for the improvement of patient management and therapeutic outcomes. The insights provided may guide future research directions and clinical practices in the fight against PCa.

Prostate basal cell carcinoma (BCC) is a rare pathologic variant with a poorly understood molecular profile. Here, we describe a case of prostate BCC and compare its genetic alterations to cases in the literature. After presenting with hematuria, our patient underwent definitive radical prostatectomy for his localized biopsy-proven BCC. Somatic and germline testing revealed mutations in PIK3R1, KMT2D, and NOTCH1, and MUTYH, NBN, and MSH3, respectively. Upon literature review, we found that prostate BCC mutations disrupt cell growth, epigenetic regulation, and cell fate determination. With no consensus guidelines available, experimental targeted therapies have shown promise for prostate BCC management.

Genomic and transcriptomic sequencing technologies have revolutionized our ability to characterize prostate cancer at the molecular level. The underlying premise of next-generation sequencing technologies and their current and evolving applications in prostate cancer management are provided in the review.

Improved methodologies are allowing timely sequencing of the coding regions or both the coding and noncoding regions of the genome to help identify potential mutations and structural variations in the prostate cancer genome, some of which are currently also targetable therapeutically. DNA microarray- based differential gene expression has been supplanted by RNA sequencing (RNA-seq), which not only allows for more accurate quantitation but also nucleotide-level resolution to investigate the entire transcriptome, including alternative gene spliced transcripts and noncoding RNA transcripts, whose full clinical implications have yet to be fully understood and realized. Gene classifier platforms that predict risk of recurrence or metastasis are being incorporated into prostate cancer management algorithms. In the appropriate clinical context, not only somatic but also germline mutation testing is being recommended.

Continued clinical integration of sequencing technologies and ongoing research will lead to improved understanding of prostate cancer biology and prostate cancer treatment.

PARP1/2 have overlapping yet non-redundant biological functions in DNA repair and AR-transcriptional regulation. Studies on PARP alterations in human tumors have yielded conflicting results. In prostate cancer (PCa), PARP1/2 protein overexpression has been related to androgen deprivation therapy (ADT) resistance, biochemical recurrence, and progression to metastases. PARP inhibitors (PARPi) have been approved for treating metastatic castration-resistant PCa with homologous recombination repair (HRR) gene mutations. However, the significance of PARP1/2 genomic alterations is not fully studied. We aimed to analyze PARP1/2 alterations in PCa, to assess their value as prognostic markers, and to explore their relevance for potential therapeutic stratification. PARP1/2 copy number status was evaluated in 121 PCa primary tumors through real time PCR. In 29 of them, a regional pelvic lymph node (RLN) involvement was also analyzed. BRCA1/2 somatic mutations were analyzed in 24 PCa. Relationship with clinicopathological features, progression to metastases, and PSA recurrence was assessed. PARP1 loss and PARP2 gain were detected in 34.7% and 32.2% of primary tumors, respectively, with a high frequency of co-occurrence (p<0.001). Both alterations were statistically associated with locally-advanced disease at diagnosis (p=0.036; p=0.006), metastatic dissemination (p=0.014; p=0.003), and other aggressive clinicopathological characteristics (as presence of Gleason pattern 5, high-grade, and high-stage). Cases with exclusive PARP2 gain had the shortest time to PSA recurrence, while double wt patients displayed the best outcome (p=0.007). In 29 paired primary tumors and RLN involvement, PARP1 loss showed strong concordance (p=0.001), whereas PARP2 gain did not (p=0.411). In conclusion, loss of PARP1 and gain of PARP2 show strong co-occurrence, and are associated with clinicopathological characteristics of aggressiveness. PARP2 alterations appear to have a particularly significant impact on disease prognosis. Furthermore, these data suggest that the analysis of PARP1/2 copy number status could be useful to predict PCa outcome. Its role on therapy warrants further evaluation.

As is the case with most solid tumors, the heterogeneity of the disease biology of prostate cancer presents clinicians managing this disease with daily challenges. However, in contrast to other common cancers such as breast, lung, and colorectal cancers, there are unique challenges in prostate cancer management, including the variety of clinicians who manage aspects of the disease (urologists, medical oncologist, radiation oncologists) and the striking absence of prospective comparative data to inform the optimal sequence of systemic therapy in patients with metastatic castration-resistant disease. The purpose of this review is to attempt to assist practicing oncologists with sorting through the myriad of prostate cancer disease subsets and the challenges in making therapeutic decisions in multiple data-free zones given the absence of level 1 comparative clinical trials in the metastatic hormone-sensitive and castration-resistant states.

Even though the introduction of 177 Lu-PSMA-617 RLT represents a major milestone in the treatment of mCRPC, there are still patients who do not respond adequately to this therapy and for whom there are only limited options left. Augmenting 177 Lu-PSMA-617 RLT with the alpha-emitter 225 Ac-PSMA-617 may present an escalating treatment option to increase efficacy. In this study, we aim to evaluate outcome and safety of 225 Ac-PSMA-617 augmentation to 177 Lu-PSMA-617 RLT in patients who present insufficient response to monotherapy with 177 Lu-PSMA-617 RLT.

The study included n = 51 mCRPC patients enrolled in a prospective registry receiving 177 Lu-PSMA-617 monotherapy and showing insufficient response, followed by initiation of 225 Ac-PSMA-617 augmentation, with adjusted activities depending on individual patient characteristics. Biochemical response, progression-free survival, and overall survival were assessed. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0).

After initiation of 225 Ac-PSMA-617 augmentation to 177 Lu-PSMA-617 RLT, 24/51 patients (47.1%) exhibited partial remission, 16/51 (31.4%) stable disease, and 11/51 (21.6%) progressive disease. The median progression-free survival and overall survival rates were 6.3 months and 9.1 months, respectively. The majority of CTCAE gradings remained stable after initiating augmentation. Severe adverse events were rare, and no treatment termination due to side effects was recorded.

225 Ac-PSMA-617 augmented 177 Lu-PSMA-617 radioligand therapy seems to be an effective escalating treatment option in patients after failure of conventional 177 Lu-PSMA-617 RLT and represents a promising approach balancing antitumor effect and tolerable side effects.

It has been shown that androgen receptor pathway inhibitor (ARPIs) treatment for metastatic castration-resistant prostate cancer (mCRPC) improves overall survival rates, but ARPIs appear to be associated with a higher frequency of treatment-related neuroendocrine prostate cancer (t-NEPC). Our aim was to quantify the proportion of prostate adenocarcinoma cases that transition to t-NEPC following ARPI therapy.

We conducted a comprehensive search of the literature on t-NEPC using databases including MEDLINE and Scopus. Eligible studies reported outcome data for NEPC in patients with prior mCRPC treated with an ARPI. To determine the pooled frequency of neuroendocrine transformation, the Freeman-Tukey variance-stabilizing arcsine transformation was applied to individual frequencies.

Among the 938 patients in eight eligible studies, t-NEPC diagnosis was confirmed in 171 patients, predominantly via pathology. Baseline biopsy verification to ensure the absence of NEPC was performed in most cases. The definition of t-NEPC varied among the studies. Five studies used a morphological definition based on histopathology, and three studies used NEPC biomarker detection on circulating tumor cells. A meta-analysis of aggregate data revealed an overall NEPC frequency following ARPI therapy of 16% (95% confidence interval 9-24%).

ARPI-related NEPC represents a frequently underdiagnosed late complication of mCRPC. Given the absence of biomarkers for diagnosis, routine repeat biopsy at the mCRPC stage should be considered to diagnose t-NEPC transitions.

Management of metastatic prostate cancer (mPCa) presents significant challenges. In this systematic review, meta-analysis, and meta-regression, the efficacy, safety, and quality of life (QoL) outcomes of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) utilising lutetium-177 ([177Lu]Lu-PSMA) and actinium-225 ([225Ac]Ac-PSMA) were assessed.

A detailed literature search across PubMed/Medline, EMBASE, Web of Science, Scopus, and Cochrane Library was conducted, culminating in the inclusion of 100 studies involving 8711 patients. Data on prostate-specific antigen (PSA) responses, toxicity profiles, and QoL and survival outcomes were analysed. Proportional meta-analyses and meta-regression analyses were performed.

The estimated proportion of patients with PSA decline ≥50% was 0.49 for [177Lu]Lu-PSMA and 0.60 for [225Ac]Ac-PSMA in mPCa, particularly metastatic castration-resistant prostate cancer. A meta-regression analysis indicated an association between the cumulative amount of administered activity and the proportion of PSA ≥50% decline. Positive PSA responses were observed alongside improved overall survival across both therapies. Our analyses also identified the key factors associated with PSA responses and survival outcomes, including baseline haemoglobin level, and the presence of visceral metastases. Although anaemia was commonly observed, with [177Lu]Lu-PSMA, severe toxicities were infrequent. Improved QoL was observed following [177Lu]Lu-PSMA therapy, whereas it remained stable following the second cycle of [225Ac]Ac-PSMA treatment. Heterogeneity across studies for PSA responses and toxicity profiles is a limitation.

Our findings suggest an association between PRLT and reductions in PSA levels, as well as associations with enhanced survival outcomes in mPCa. Furthermore, our analysis shows a low incidence of severe toxicity associated with this treatment. These observations highlight the important role of PRLT in the management of mPCa.

This study described treatment patterns, reasons for treatment, and homologous recombination repair mutation (HRRm) testing patterns in a real-world metastatic castration-resistant prostate cancer (mCRPC) population in Europe.

Data were drawn from the Adelphi Prostate Cancer Disease Specific Programme™, a cross-sectional survey of physicians and patients conducted in France, Germany, Italy, Spain, and the United Kingdom, November 2022-May 2023. Physicians provided clinical characteristics, treatment and HRRm testing patterns, and reasons for treatment for eight consecutive patients with mCRPC. Most analyses were descriptive; treatment reasons were compared using Fisher's Exact test.

Physicians provided data for 1,737 mCRPC patients. Most patients (73%) were androgen receptor pathway inhibitor (ARPi)-naïve at first-line (1 L) mCRPC. Here, at 1 L mCRPC, 60% of patients received ARPi and 24% chemotherapy. Of those who received ARPi prior to mCRPC (n = 291), 60% received chemotherapy at mCRPC and 21% ARPi. Overall, 37% were HRRm tested. Treatment patterns, sequencing, reasons, and HRRm testing varied by country, physician specialty, and practice setting.

Treatment patterns generally followed guidelines. ARPi prescriptions prior to mCRPC were numerically higher than previously reported, however HRRm testing rates were still low meaning mCRPC patients may miss out on more effective targeted treatments.

Intraductal Carcinoma of the Prostate (IDC-P) is a significant prognostic indicator for prostate cancer, which demonstrates significant associations with homologous recombination repair gene mutations (HRRm) and alterations in tumor suppressor genes. However, no study in Japan has investigated the association between IDC-P and genetic mutations in men with metastatic castration-sensitive prostate cancer (mCSPC).

This prospective observational study enrolled 102 de novo mCSPC (LATITUDE high-risk) patients diagnosed between 2018 and 2021, with subsequent monitoring of survival outcomes. A single genitourinary pathologist evaluated all needle biopsy slides. Genetic analyses were performed using the Myriad myChoice HRD plus™. These genetic analyses covered 108 genetic loci, including 15 HRRm genes, with a success rate of 91%.

Genetic alterations were observed in 79 patients (77.5%), with 20 exhibiting HRRm (19.6%). Common genetic alterations included FOXA1 (29.4%) and TP53 (17.6%) mutations; BRCA (9.8%) mutations were the most frequent HRRm (BRCA1:2 cases, BRCA2:8 cases, including 6 biallelic). IDC-P-positive patients demonstrated a significantly higher frequency of genetic aberrations (82.6% vs. 50%, p = 0.0082). Patients with biallelic BRCA2, TP53, and PTEN mutations exhibited significantly poorer cancer-specific survival. Multivariate analysis identified lactate dehydrogenase (LDH) (HR 1.005, p = 0.035), TP53 mutations (HR 5.196, p < 0.001), biallelic BRCA2 mutations (HR 10.686, p = 0.005), and IDC-P as independent predictors of poor cancer-specific survival. No cancer-related deaths occurred in IDC-P-negative cases.

Our study emphasizes the significant association between IDC-P and an elevated incidence of genetic alterations in Japanese mCSPC patients, emphasizing the need for early genetic testing to guide therapeutic decision-making.

Prostate cancer is a leading malignancy among men. While early-stage prostate cancer can be effectively managed, metastatic prostate cancer remains incurable, with a median survival of 3-5 years. The primary treatment for advanced prostate cancer is androgen deprivation therapy (ADT), but resistance to ADT often leads to castrationresistant prostate cancer (CRPC), presenting a significant therapeutic challenge. The advent of precision medicine has introduced promising new treatments, including PARP inhibitors (PARPi), which target defects in DNA repair mechanisms in cancer cells. PARPi have shown efficacy in treating advanced prostate cancer, especially in patients with metastatic CRPC (mCRPC) harboring homologous recombination (HR)-associated gene mutations. Despite these advancements, resistance to PARPi remains a critical issue. Here, we explored the primary mechanisms of PARPi resistance in prostate cancer. Key resistance mechanisms include homologous recombination recovery through reverse mutations in BRCA genes, BRCA promoter demethylation, and non-degradation of mutated BRCA proteins. The tumor microenvironment and overactivation of the base excision repair pathway also play significant roles in bypassing PARPi-induced synthetic lethality. In addition, we explored the clinical implications and therapeutic strategies to overcome resistance,emphasizing the need for precision medicine approaches. Our findings highlight the need for comprehensive strategies to improve PARPi sensitivity and effectiveness,ultimately aiming to extend patient survival and improve the quality of life for those with advanced prostate cancer. As our understanding of PARPi resistance evolves, more diverse and effective individualized treatment regimens will emerge.

To describe the effectiveness and safety of olaparib off-label indications in patients with impaired homologous recombination genes and solid tumors different than those authorized.

A single-center, observational and retrospective study including patients treated with olaparib for off-label use. The main variables were patient characteristics, prior therapies, response to therapy, progression-free survival, overall survival and adverse events.

A total of 6 patients were included. All patients had metastases and received 3 or more lines of prior treatment. The primary tumor locations and mutations were partner and localizer of BRCA2 (PALB2) intrahepatic cholangiocarcinoma, ataxia telangiectasia mutated (ATM) non-small cell lung adenocarcinoma, somatic breast cancer gene (sBRCA2) colorectal cancer, germinal breast cancer gene 2 (gBRCA2) breast neuroendocrine tumor, gBRCA2 ampullary cancer and gBRCA2 pancreatic neuroendocrine tumor. At the end of the study, one patient was still receiving olaparib showing more than 25 months of sustained stable disease response. No novel toxicities were observed besides those included in the product information.

There is limited published evidence on the use of olaparib in patients harboring pathogenic variants other than breast cancer genes, like PALB2 and ATM and conditions different than those authorized such as digestive tract, neuroendocrine and lung tumors. Further research is to assess the efficacy of olaparib in these patients.

Prostate Cancer (PrCa) is one of the most common cancers worldwide and causes a significant healthcare burden. Recent predictions estimate the incidence of new cases of PrCa will double from 1.4 million in 2020 to 2.9 million by 2040.The known risk factors for PrCa are increasing age, family history, ancestry and genetics. PrCa is one of the most heritable of the more common cancers. The heritability of PrCa is due to both rare moderate to high-risk monogenic variants and more common variants known as single nucleotide polymorphisms (SNPs) which can be used to calculate a polygenic risk score (PRS) for PrCa, while there is some of the genetic risk as yet unexplained. In recent years more PrCa risk-associated SNPs have been identified, increasing over time with the inclusion of more persons of diverse ancestry in studies. The identification of germline variants known to be associated with increased PrCa risk and disease aggressiveness has led to targeted treatments for certain pathogenic variant carriers.This is a mini review of how the genetics of PrCa can impact on screening and early detection of the disease and the treatment and management of the disease when diagnosed.

Matched targeted therapies (MTT) given alone or in combination with systemic anti-cancer therapies have delivered proven survival benefit for many people with newly diagnosed cancer. However, there is little evidence of their effectiveness in the recurrent or late-stage setting. With this uncertainty, alongside the perception that late-stage cancers are too genetically heterogenous or too mutationally diverse to benefit from matched targeted therapies, next-generation sequencing (NGS) of tumours in people with refractory cancer remains a low priority. As a result, next-generation sequencing testing of recurrent or late-stage disease is discouraged. We lack evidence to support the utility of next generation sequencing in guiding matched targeted therapies in this setting.

To evaluate the benefits and harms of matched targeted therapies in people with advanced cancers in randomised controlled trials.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform (WHO-ICTRP) search portal up to 30th October 2024. We also screened reference lists of included studies and also the publications that cited these studies.

We included randomised controlled trials (RCTs) that had enroled participants with advanced/refractory solid or haematological cancers who had progressed through at least one line of standard anti-cancer systemic therapy. To be eligible, all participants should have received matched targeted therapy based on next-generation sequencing carried out on their tumour (tumour tissue, blood or bone marrow).

We systematically searched medical databases (e.g. MEDLINE, Embase) and trial registers for randomised controlled trials (RCTs). Outcomes of interest were progression-free survival (PFS), overall survival (OS), overall response rates (ORR), serious (grade 3 or 4) adverse events (AEs) and quality of life (QOL). We used a random-effects model to pool outcomes across studies and compared predefined subgroups using interaction tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty was used to evaluate the quality of evidence.

We identified a total of 37 studies, out of which 35 studies (including 9819 participants) were included in the meta-analysis. All included studies compared a matched targeted therapy intervention to standard-of-care treatment, non-matched targeted therapies or no treatment (best supportive care): Matched targeted therapy versus standard-of-care treatment Matched targeted therapy (MTT) compared with standard systematic therapy probably reduces the risk of disease progression by 34% (hazard ratio (HR) = 0.66, 95% confidence interval (CI) 0.59 to 0.74; 14 studies, 3848 participants; moderate-certainty evidence). However, MTT might have little to no difference in risk of death (HR = 0.85, 95% CI 0.75 to 0.97; 14 studies, 3848 participants; low-certainty evidence) and may increase overall response rates (low-certainty evidence). There was no clear evidence of a difference in severe (grade 3/4) adverse events between matched targeted therapy and standard-of-care treatment (low-certainty evidence). There was limited evidence of a difference in quality of life between groups (very low-certainty of evidence). Matched targeted therapy in combination with standard-of-care treatment versus standard-of-care treatment alone Matched targeted therapy in combination with standard-of-care treatment compared with standard-of-care treatment alone probably reduces the risk of disease progression by 39% (HR = 0.61, 95% CI 0.53-0.70, 14 studies, 2,637 participants; moderate-certainty evidence) and risk of death by 21% (HR = 0.79, 95% CI 0.70 to 0.89; 11 studies, 2575 participants, moderate-certainty evidence). The combination of MTT and standard-of-care treatment may also increase overall response rates (low-certainty evidence). There was limited evidence of a difference in the incidence of severe adverse events (very low-certainty evidence) and quality of life between the groups (very low-certainty of evidence). Matched targeted therapy versus non-matched targeted therapy Matched targeted therapy compared with non-matched targeted therapy probably reduces the risk of disease progression by 24% (HR = 0.76, 95% CI 0.64 to 0.89; 3 studies, 1568 participants; moderate-certainty evidence) and may reduce the risk of death by 25% (HR = 0.75, 95% CI 0.65 to 0.86, 1307 participants; low-certainty evidence). There was little to no effect on overall response rates between MTT and non-MTT. There was no clear evidence of a difference in overall response rates (low-certainty evidence) and severe adverse events between MTT and non-MTT (low-certainty evidence). None of the studies comparing MTT and non-MTT reported quality of life. Matched targeted therapy versus best supportive care Matched targeted therapy compared with the best supportive care (BSC) i.e. no active treatment probably reduces the risk of disease progression by 63% (HR 0.37, 95% CI 0.28 to 0.50; 4 studies, 858 participants; moderate-certainty evidence). There was no clear evidence of a difference in overall survival between groups (HR = 0.88, 95% CI 0.73 to 1.06, 3 studies, 783 participants; low-certainty evidence). There was no clear evidence of a difference in overall response rates (very low-certainty of evidence) and incidence of severe adverse events (very low-certainty of evidence) between the groups. Quality of life was reported in a single study but did not provide composite scores. Risk of bias The overall risk of bias was judged low for eight studies, unclear for two studies, and the remaining 27 studies were high risk.

Matched targeted therapies guided by next-generation sequencing in people with advanced cancer prolongs the time before cancer progresses compared to standard therapies. However, there is limited evidence to suggest that it prolongs overall survival, improves the quality of life or increases adverse events. Importantly, this review supports equitable access to next-generation sequencing technology for all people with advanced cancer and offers them the opportunity to access genotype-matched targeted therapies.

In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated (ATM) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo, and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients.

Prostate cancer is the most common cancer and remains a leading cause of cancer-related deaths among men worldwide. Androgen deprivation therapy continues to be the cornerstone of treatment for prostate cancer. However, the efficacy of this treatments is often limited, leading to the emergence of drug resistance and tumor recurrence. TAK-901, an inhibitor of Aurora kinase B, has been shown to inhibit tumor growth both in vitro and in vivo models. To date, the effect of TAK-901 on prostate cancer and the underlying mechanism remain unknown. In this study, we found that TAK-901 could inhibit proliferation, colony formation and migration, while also inducing apoptosis in prostate cancer cells. We further demonstrated that TAK-901 activates the CHK1 signaling pathway, leading to G2/M-phase arrest in these cells. Additionally, we identified EPHA2 as a novel therapeutic target of TAK-901. By mutating the binding sites between EPHA2 and TAK-901, we discovered that these mutations could reverse the anti-proliferative effects of TAK-901 in prostate cancer models. Our study is the first to reveal that TAK-901 induces apoptosis in prostate cancer cells and inhibits cell growth by targeting EPHA2. These findings provide valuable insights into the underlying mechanisms of TAK-901 and may develop its therapeutic applications in prostate cancer.

Glioblastoma (GBM) is an aggressive malignant brain tumor with almost inevitable recurrence despite multimodal management with surgical resection and radio-chemotherapy. While several genetic, proteomic, cellular, and anatomic factors interplay to drive recurrence and promote treatment resistance, the epigenetic component remains among the most versatile and heterogeneous of these factors. Herein, the epigenetic landscape of GBM refers to a myriad of modifications and processes that can alter gene expression without altering the genetic code of cancer cells. These processes encompass DNA methylation, histone modification, chromatin remodeling, and non-coding RNA molecules, all of which have been found to be implicated in augmenting the tumor's aggressive behavior and driving its resistance to therapeutics. This review aims to delve into the underlying interactions that mediate this role for each of these epigenetic components. Further, it discusses the two-way relationship between epigenetic modifications and tumor heterogeneity and plasticity, which are crucial to effectively treat GBM. Finally, we build on the previous characterization of epigenetic modifications and interactions to explore specific targets that have been investigated for the development of promising therapeutic agents.

Poly (ADP-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of many cancers. Metastatic castration-resistant prostate cancer (mCRPC) is an area where PARP inhibitors are intensively studied; the efficacy with PARP inhibitor monotherapy in patients with homologous recombination repair mutations following novel hormonal therapy have prompted the investigation of combination therapy, with adding an androgen receptor pathway inhibitor (ARPI) being one focus of research. Data on PARP inhibitor monotherapy and combination therapy for mCRPC are accumulating, and it is important to navigate through the complex data to inform treatment decision. Here we review the mechanisms of action of PARP inhibitors, their pharmacological properties, the synergistic activity of PARP inhibitors plus other drug classes, and the clinical evidence on monotherapy and combination therapy in patients with mCRPC. We propose key considerations in the selection of agents and treatment sequence for mCRPC, such as efficacy, toxicity profiles, biomarkers, and interactions with concomitant medications.

PARP inhibitors are effective in treating ovarian cancer, especially for BRCA1/2 pathogenic variant carriers and those with HRD (homologous recombination deficiency). Concerns over toxicity and costs have led to the search for predictive biomarkers. We present an updated systematic review, expanding on a previous ESMO review on PARP inhibitor biomarkers.

Following ESMO's 2020 review protocol, we extended our search to March 31, 2023, including PubMed and clinical trial data. We also reviewed the reference lists of review articles. We conducted a meta-analysis using a random-effects model to evaluate hazard ratios and assess the predictive potential of biomarkers and the effectiveness of PARP inhibitors in survival.

We found 375 articles, 103 of which were included after screening (62 primary research, 41 reviews). HRD remained the primary biomarker (95%), particularly BRCA1/2 variants (77%). In the non-HRD category, six articles (10%) introduced innovative biomarkers, including ADP-ribosylation, HOXA9 promoter methylation, patient-derived organoids, KELIM, and SLFN11.

Prospective assessment of real-time homologous recombination repair via nuclear RAD51 levels shows promise but needs validation. Emerging biomarkers like ADP-ribosylation, HOXA9 promoter methylation, patient-derived organoids, KELIM, and SLFN11 offer potential but require large-scale validation.

Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for Africans. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising clinico-methodologically matched deep-sequenced whole-genome data for 113 African versus 57 European PCa patients, we interrogate 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identify 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair MLH1 and BARD1 and tumour suppressors FOXP1, WASF1 and RB1. Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African-associated disparity.

The treatment of metastatic castration-resistant prostate cancer (mCRPC) has been rapidly evolving over the last two decades. The advent of new androgen receptor pathway inhibitors (ARPIs) such as abiraterone acetate or enzalutamide marks a great advance for treating mCRPC patientd in the pre- and post-docetaxel settings. The subsequent approval of ARPIs in early stages-i.e., metastatic hormone-sensitive (mHSPC) or nonmetastatic CRPC-led to a realignment of subsequent treatment choices upon progression to mCRPC, given the possibility of cross-resistance between ARPIs. Therapies with mechanisms of action different from those of ARPIs are now the focus of new treatment developments. Also, this anomalous situation brings the focus back to well-known treatments currently used later in the treatment sequence. This is the case of radium-223 which, when administered with enzalutamide, has recently been shown to prolong radiographic progression-free survival vs. enzalutamide alone in the first line in asymptomatic or mildly symptomatic patients with no known visceral metastases. In this narrative review, we summarize the treatment landscape for mCRPC, both from a historical and practical point of view, to understand the new potential of radium-223 as a treatment option in this setting.

Interdisciplinary tumor boards (ITB) are essential in optimizing treatment recommendations for metastatic castration-resistant prostate cancer (mCRPC) by incorporating oncology guidelines, clinical trials, and patient-specific factors to ensure individualized care. This study examines clinical parameters that influence ITB recommendations, evaluates their adherence to guidelines, and assesses their impact on patient survival.

In a retrospective analysis, data from 187 mCRPC patients discussed at an ITB in a tertiary care center in 2018 were evaluated. Patient- and disease-specific factors were correlated with adherence to National Comprehensive Cancer Network® (NCCN®) guidelines and overall survival (OS). The impact of clinical parameters on survival outcomes was assessed through univariate and multivariate analyses.

The median patient age was 72.8 years, with a median prostate-specific antigen (PSA) level of 65.0 ng/ml. Guideline-compliant recommendations were given in 42.9% of cases, while 57.1% received individualized recommendations. Clinical trial eligibility was noted in 24.8% of patients. Individualized ITB recommendations were associated with significantly longer OS (38.3 vs. 21.2 months, p = 0.03). Shorter OS correlated with renal impairment (p = 0.007), symptomatic metastases (p < 0.0001), and visceral metastases (p < 0.0001). Limitations include the retrospective design, lack of follow-up on therapy adherence, and absence of progression-free survival (PFS) data.

ITB discussions improve survival in mCRPC patients, mainly due to personalized approaches and better access to clinical trials. Visceral and symptomatic metastases as well as renal impairment are risk factors for reduced OS, emphasizing the need for careful management of these high-risk patients. The results support the expanded use of ITB to improve mCRPC treatment outcomes.

To determine the performance of a multi-gene copy number variation (MG-CNV) risk score in metastatic tissue and plasma biospecimens from treatment-naïve metastatic castration-resistant prostate cancer (mCRPC) patients for prediction of clinical outcomes.

The mCRPC tissue and plasma cell-free DNA (cfDNA) biospecimen sequencing results obtained from publicly accessed cohorts in dbGaP, cBioPortal, and an institutional mCRPC cohort were used to develop a MG-CNV risk score derived from gains in AR, MYC, COL22A1, PIK3CA, PIK3CB, NOTCH1 and losses in TMPRSS2, NCOR1, ZBTB16, TP53, NKX3-1 in independent cohorts for determining overall survival (OS), progression-free survival (PFS) to first-line androgen receptor pathway inhibitors (ARPIs). The range of the risk scores for each cohort was dichotomized into "high-risk" and "low-risk" groups and association with OS/PFS determined. Univariate and multivariable Cox proportional hazards regressions were applied for survival analyses (P < .05 for statistical significance).

Of 1137 metastatic tissue-plasma biospecimens across all cohorts, 699/1137 were treatment-naive mCRPC (235/699 metastatic tissue; 464/699 plasma-cfDNA), and 311/1137 were matched tissue-cfDNA pairs. In multivariable analysis, the MG-CNV risk score derived from metastatic tissue or in cfDNA was statistically significantly associated with OS with high score associated with short survival (hazard ratio = 2.65, confidence interval = 1.99 to 3.51; P = 1.35-11) and shorter PFS to ARPIs (median PFS of 7.8 months) compared with 14 months in patients with low-risk score.

A molecular risk score in treatment-naïve mCRPC state obtained either in metastatic tissue or cfDNA predicts clinical survival outcomes and offers a tumor biology-based tool to design biomarker-based enrichment clinical trials.

PARP inhibitors are a class of agents that have shown significant preclinical activity in models defective in homologous recombination (HR). The identification of synthetic lethality between HR defects and PARP inhibition led to several clinical trials in tumors with known HR defects (initially mutations in BRCA1/2 genes and subsequently in other genes involved in HR). These studies demonstrated significant responses in breast and ovarian cancers, which are known to have a significant proportion of patients with HR defects. Since the approval of the first PARP inhibitor (PARPi), olaparib, several other inhibitors have been developed, expanding the armamentarium available to clinicians in this setting. The positive results obtained in breast and ovarian cancer have expanded the use of PARPi in other solid tumors with HR defects, including prostate and pancreatic cancer in which these defects have been identified. The clinical trials have demonstrated responses to PARPi which are now also available for the subset of patients with prostate and pancreatic cancer with HR defects. This review summarizes the results obtained in solid tumors with PARPi and their potential use when combined with other agents, including immune checkpoint inhibitors that are likely to further increase the survival of these patients which still needs a dramatic improvement.

Intratumour hypoxia is a feature of all heterogenous solid tumours. Increased levels or subregions of tumour hypoxia are associated with an adverse clinical prognosis, particularly when this co-occurs with genomic instability. Experimental evidence points to the acquisition of DNA and chromosomal alterations in proliferating hypoxic cells secondary to inhibition of DNA repair pathways such as homologous recombination, base excision repair and mismatch repair. Cell adaptation and selection in repair-deficient cells give rise to a model whereby novel single-nucleotide mutations, structural variants and copy number alterations coexist with altered mitotic control to drive chromosomal instability and aneuploidy. Whole-genome sequencing studies support the concept that hypoxia is a critical microenvironmental cofactor alongside the driver mutations in MYC, BCL2, TP53 and PTEN in determining clonal and subclonal evolution in multiple tumour types. We propose that the hypoxic tumour microenvironment selects for unstable tumour clones which survive, propagate and metastasize under reduced immune surveillance. These aggressive features of hypoxic tumour cells underpin resistance to local and systemic therapies and unfavourable outcomes for patients with cancer. Possible ways to counter the effects of hypoxia to block tumour evolution and improve treatment outcomes are described.

Aim of this study was to analyze the safety of prostate-specific membrane antigen radioligand therapy (PSMA-RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC) with preexisting moderate to severe thrombocytopenia (CTCAE ≥ 2).

Seventeen mCRPC patients with preexisting thrombocytopenia (platelet count < 75 × 109/L) were included in this study. Patients received a median of 3 cycles of [177Lu]Lu-PSMA-617 (range 1-6). The course of platelet cell count was closely monitored within and after the PSMA-RLT and analyzed statistically and according to CTCAE.

No significant difference in platelet counts was observed between baseline and follow-up after each PSMA-RLT cycle: first cycle (54.18 ± 16.07 at baseline vs. 59.65 ± 39.16 at follow up [in × 109/L], p=  0.834), second cycle (58.56 ± 16.43 vs. 107.1 ± 56.44, p = 0.203), and third cycle (60.38 ± 16.57 vs. 132.1 ± 80.43, p = 0.148), respectively. Similarly, baseline and end of treatment values, irrespective of the number of administered cycles, did not reveal a significant difference (54.18 ± 16.07 vs. 72.06 ± 71.9, p = 0.741). After the end of therapy, irrespective of the number of administered cycles, 29.4% of patients remained stable in terms of CTCAE scoring, 41.2% changed to a higher score and 29.4% improved to a lower score. We observed no critical bleeding events due to thrombocytopenia.

Despite the common consideration of marked preexisting thrombocytopenia as a contraindication for RLT, this study indicates feasibility of PSMA-RLT in patients with preexisting thrombocytopenia of grade ≥ 2, as in our preliminary experience, there was no RLT-induced significant deterioration of platelet cell count. Thus, patients with thrombocytopenia should not be categorically excluded from receiving PSMA-RLT.

Uterine sarcomas are rare, aggressive tumors with limited chemotherapy responsiveness. Poly(ADP-ribose) polymerase inhibitors (PARPis) have emerged as targeted therapies for patients with BRCA mutations across multiple cancer types, with anecdotal responses in uterine sarcoma. This retrospective, single-center study aims to describe relevant genomic and clinical features of patients with BRCA-altered uterine sarcoma and the efficacy of PARPis in this population.

Eligible patients included all histopathologically confirmed uterine sarcoma with pathogenic BRCA alterations identified through Memorial Sloan Kettering Cancer Center-integrated mutation profiling of actionable cancer targets, excluding carcinosarcoma. Genomic, pathologic, and treatment information was extracted from the cBioPortal database and chart review.

Thirty-five patients were identified with uterine sarcoma harboring pathogenic BRCA alterations, including 33 BRCA2 alterations (70% homozygous deletions, 3% structural variants, 27% mutations) and two BRCA1 mutations. Leiomyosarcoma (LMS) was the most common histology (86%). Thirteen patients with uterine LMS were treated with PARPis in the recurrent/metastatic therapy setting (54% combination therapy regimens) with an overall response rate (ORR) of 46% (1 of 6 for PARPi monotherapy, 5 of 7 for PARPi combination regimens), a clinical benefit rate (CBR) of 62%, and a median progression-free survival (PFS) of 13.2 months (range, 1.0-71.9). The median PFS ratio compared with previous systemic therapy was 1.9 (range, 0.4-53.9), and 58% had a PFS ratio of ≥1.3. The median time on PARPi was 14.5 months (range, 1.3-71.9). The ORR for patients with somatic BRCA2 deletions was 60% (n = 6 of 10), with a CBR of 80% (n = 8 of 10). One patient with metastatic disease and progression on previous hormonal and chemotherapy demonstrated a complete response to PARP/PD-L1 inhibitor combination therapy, ongoing for 70+ months.

PARPis demonstrate promising efficacy in patients with uterine LMS with somatic BRCA2 deletions.

In the over 80 years since androgens were found to play a pivotal role in prostate cancer (PCa) progression, androgen deprivation therapy (ADT) has been a cornerstone in treating advanced PCa. Castration-resistant PCa persists, however, with some of these tumors evolving to androgen receptor (AR)-independent forms like neuroendocrine PCa. The development of novel diagnostic and therapeutic approaches to PCa is therefore crucial. This review provides an overview of recent basic research in PCa, focusing on two main areas: PCa cells and their tumor microenvironments. The first section describes current knowledge on the intricate mechanisms of AR signaling pathways, emphasizing the roles of coactivators and chromatin state alterations in gene regulation. Genomic analyses have revealed recurrent mutations and copy number alterations critical for precision medicine. Liquid biopsy has become a promising tool for real-time tumor monitoring, identifying genetic alterations in circulating-tumor DNA or extracellular vesicles. The second section describes the tumor microenvironment of PCa, highlighting its immunosuppressive landscape and the potential of combining ADT with immunotherapy. Advanced techniques, including single-cell RNA sequencing and spatial transcriptomics offer insights into cellular heterogeneity and interactions within the tumor microenvironment, paving the way for novel therapeutic strategies. Integration of these diverse research areas will provide a comprehensive understanding of the current state and future directions of PCa research, underscoring the importance of personalized medicine and the dynamic nature of cancer treatment strategies.

In recent years, immunotherapy has shown significant therapeutic potential in patients with advanced tumors. However, only a small number of individuals benefit, mainly due to the tumor microenvironment (TME), which provides conditions for the development of tumors. Macrophages in TME, known as tumor-associated macrophages (TAM), are mainly divided into M1 anti-tumor and M2 pro-tumor phenotypes, which play a regulatory role in various stages of tumorigenesis, promote tumorigenesis and metastasis, and cause immunotherapy resistance.

This review focuses on research strategies and preclinical/clinical research progress in translating TAM into antitumor phenotype by referring to the PubMed database for five years. These include small molecule chemotherapy drug development, metabolic regulation, gene editing, physical stimulation, nanotechnology-mediated combination therapy strategies, and chimeric antigen receptor-based immunotherapy.

It is necessary to explore the surface-specific receptors and cell signaling pathways of TAM further to improve the specificity and targeting of drugs and to strengthen research in the field of probes that can monitor changes in TAM in real time. In addition, the physical stimulation polarization strategy has the advantages of being noninvasive, economical, and stable and will have excellent clinical transformation value in the future.

There is no cross-sectional comparison on therapeutic and adverse effects for treatments of metastatic castration-resistant prostate cancer (mCRPCa). We aimed to horizontally compare them for all common first-line and second-line therapies.

We conducted a network meta-analysis with a systematic review in four databases (Pubmed, Web of Science, Embase, and Cochrane Library) up to January 5th, 2025. All randomized controlled trials (RCT) related to mCRPCa treatments with a clear description in study design were included. Endpoints included the radiographic progression-free survival (rPFS), overall survival (OS), time to PSA progression (TTPP), PSA progression rate (PSARR), and adverse events. All data was extracted by two researchers and analyzed with Gemtc package in R and Stata15. This NMA protocol was registered online (ID: CRD42025633178).

After screening among 33,694 articles, 24 RCTs involving 13,059 cases were included. For first-line treatments, combination therapies with second-generation androgen receptor inhibitors (ARIs) showed superior efficacies in OS [HR of poly(ADP-ribose) polymerase inhibitors (PARPi) + ARI: 0.63 (0.32,1.25)], TTPP [HR of Lu177 + ARI: 0.07 (0.01,0.87)] and PSARR [RR of Lu177 + ARI: 33.02 (15.56,71.62)] with the highest SUCRA (Surface under the Cumulative Ranking Curve) (72%, 91% and 97% respectively). PARPi + ARI also performed best for rPFS (SUCRA: 85%, with an insignificant HR [0.12 (0.02,2.35)]. For post-docetaxel second-line treatments, ARI also emerged as the preferred option. Efficacies of post-ARI second-line treatments were not evaluated due to the lack of related RCTs. No obvious heterogeneity and publication bias was detected during the therapeutic comparison.

This study provided comparative evidence for first-line and post-chemotherapy second-line mCRPCa treatment options. Second-generation ARIs exhibited good efficacy, particularly when combined with other treatments. However, the safety analysis necessitated balance between benefits and adverse events, especially for combination therapies. Stronger evidence is needed through direct comparisons in future clinical trials.

The study was supported by The National Natural Science Foundation of China (No. 82172568).

A better understanding of the molecular alterations that underlie urologic malignancies and advances in targeted therapies has impacted classification, prognostication, and treatment. In bladder tumors, these advances include the development of antibody-drug conjugates targeting nectin-4 and Trop-2, as well as human epidermal growth factor receptor 2 and immunotherapy. In prostate cancer, assessment of the percentage of Gleason pattern 4, presence of cribriform glands, and molecular alterations, including PTEN and mismatch repair protein loss, have become standard for clinical care. In renal malignancies, alterations in TSC1/2, mammalian target of rapamycin, anaplastic lymphoma kinase, and other genes impact classification and therapeutic decisions.

Prostate cancer guidelines recommend molecular analysis of biomaterial following resistance to first-line systemic therapy in order to identify druggable mutations. We report on our results of molecular analysis of tissue specimens via next generation sequencing (NGS) in men with metastatic castration resistant prostate cancer (mCRPC).

In all, 311 mCRPC patients underwent NGS analysis from biopsy samples of progressive metastatic lesions or archival radical prostatectomy specimens. NGS analysis was either performed using a panel of 18 prostate cancer-specific amplicons or via the TS0500 panel.

Of the 311 biopsies, 299 (96%) revealed sufficient DNA content for NGS analysis independent on the specimen origin. Biopsies were taken from prostate (31%), lymph nodes (26%), visceral (17%) or osseous (18%) metastases. In 223 (75%) and 76 (25%) patients activating/inhibiting and no mutations were identified, respectively. Most frequently, mutations of HRD genes including a positive HRD score and p53 were identified in 22% of patients each. About 50% of HRD gene mutations were pathogenic and treatment with PARP inhibitors was initiated. Although the majority of p53 alterations were inactivating mutations, 3 patients demonstrated gain-of-function mutations resulting in an inactivation of ATM. Activating androgen receptor mutations and inactivating PTEN mutations were identified in 42 (14%) and 24 (8%) patients, respectively. Specific AR mutations resulted in a switch of hormonal therapy. Mutations of mismatch repair deficiency genes/MSI high were identified in 5 patients resulting in the administration of pembrolizumab. Addition of the TSO 500 panel identified additional mutations in 4.5% of patients and only 2% of the total cohort would have benefitted from this large panel with the identification of druggable mutations.

Druggable mutations were identified in one third of mCRPC patients using an 18 amplicon-panel analyzed via NGS. Based on our data, molecular analysis of AR mutations or mutations of the HRD genes should be performed following progression after first-line hormonal therapy. A more extensive molecular analysis seems to be useful following progression to the standard sequential hormonal, cytotoxicand radioligand therapies. Use of the expensive TSO 500 panel seems to be of additional therapeutic value in only a minority of patients.

Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, such as olaparib, talazoparib, rucaparib, and niraparib, comprise a therapeutic class that targets PARP proteins involved in DNA repair. Cancer cells with homologous recombination repair defects, particularly BRCA alterations, display enhanced sensitivity to these agents because of synthetic lethality induced by PARP inhibitors. These agents have significantly improved survival outcomes across various malignancies, initially gaining regulatory approval in ovarian cancer and subsequently in breast, pancreatic, and prostate cancers in different indications. This review offers a comprehensive clinical overview of PARP inhibitor approvals, emphasizing their efficacy across different cancers based on landmark phase 3 clinical trials.

Cancer is an abnormal and uncontrolled proliferation of normal cells. The availability of safer anticancer drugs with exceptional selectivity for healthy cells and great efficacy against various cancer forms continues to be a significant obstacle. The piperazine moiety is used as the building block of several molecules and is reported to have the ability to inhibit the cell cycle (G1/S phase), inhibit angiogenesis, and interact with DNA. Piperazine also has a flexible binding feature that allows it to interact with a variety of biological targets, which makes it effective against cancers. As there is a continuous need to obtain an anticancer drug with improved efficacy and fewer side effects, the piperazine derivatives attract the attention of researchers. This review highlights the recently reported methods of synthesis of fused/substituted piperazines, structure-activity relationship, and interactions with targets/receptors as anticancer agents. Thus, the presented review will help medicinal chemists in designing anticancer molecules with piperazines.

The treatment landscape of prostate cancer is quite complex because of the many therapeutic options available in different disease settings (hormonal treatments, chemotherapy, poly(adenosine diphosphate ribose) polymerase inhibitors, radiopharmaceutical therapy). Since in most cases we do not have comparative studies between these different agents, the best therapeutic sequence in patients with prostate cancer remains unsolved. In this review, we describe the different systemic therapeutic options available in each disease setting from localized disease to metastatic castration-resistant disease. We also indicate when to use each of these therapeutic options in the therapeutic sequence on the basis of the results of the available studies. A special focus of this review is the place of prostate-specific membrane antigen radiopharmaceutical therapy in the treatment algorithms.

Despite the boom in the development of cancer management in the last decade, most patients with metastatic prostate cancer (PCa) eventually progress to metastatic castration-resistant PCa (mCRPC) and often require multiple lines of treatment. The treatment landscape of mCRPC has evolved rapidly in recent years, introducing various types of systemic therapies, including taxane-based chemotherapy, androgen receptor pathway inhibitors, bone-targeted radionuclides (e.g., radium-223), immune checkpoint inhibitors, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, and radioligand therapies (RLTs) [e.g., a prostate-specific membrane antigen (PSMA) ligand labelled with 177Lu].

To help clinicians navigate the increasingly complex treatment landscape of mCRPC, this article reviews the evidence on different therapeutic regimens from pivotal trials. In addition, it reports on the results of a questionnaire developed and distributed by the Hong Kong Society of Uro-Oncology (HKSUO), with the aim of collecting the perspectives of specialists experienced in the treatment of advanced PCa in Hong Kong with regard to the clinical application of RLT, primarily [177Lu]Lu-PSMA-617/analogue therapy.

A total of 43 questionnaire respondents (including clinical oncologists, urologists, nuclear medicine specialists, and medical oncologists) voted on 27 consensus questions divided into eight sections. Consensus or strong consensus (correspondingly ≥75% or ≥90% acceptance for an answer option) was reached for 10 questions. Subsequently, a panel of 13 local and overseas experts coordinated by the HKSUO discussed the voting results and provided further insights into certain questions.

The literature review, the voting results of the questionnaire, and the expert opinions are expected to facilitate better understanding of recent therapeutic advancements and the role of novel RLTs in the treatment of mCRPC among clinicians.

Cells deficient in DNA repair factors breast cancer susceptibility 1/2 (BRCA1/2) or ataxia-telangiectasia mutated (ATM) are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Building on our previous findings, we asked how the lysine methyltransferase SETD1A contributed to PARP inhibitor-mediated cell death in these contexts and determined the mechanisms responsible.

We used cervical, breast, lung and ovarian cancer cells bearing mutations in BRCA1 or ATM and depleted SETD1A using siRNA or CRISPR/Cas9. We assessed the effects of the PARPi Olaparib on cell viability, homologous recombination, and DNA repair. We assessed underlying transcriptional perturbations using RNAseq. We used The Cancer Genomics Atlas (TCGA) and DepMap to investigate patient survival and cancer cell characteristics.

Loss of SETD1A from both BRCA1-deficient and ATM-deficient cancer cells was associated with resistance to Olaparib, explained by partial restoration of homologous recombination. Mechanistically, SETD1A-dependent transcription of the crossover junction endonuclease EME1 correlated with sensitivity to Olaparib in these cells. Accordingly, when SETD1A or EME1 was lost, BRCA1 or ATM-mutated cells became resistant to Olaparib, and homologous recombination was partially restored.

Loss of SETD1A or EME1 drives cellular resistance to Olaparib in certain genetic contexts and may help explain why patients develop resistance to PARP inhibitors in the clinic.

Cabazitaxel (CAZ) has been shown to prolong overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel treatment. However, the impact of the number of prior androgen receptor pathway inhibitors (ARPIs) on CAZ efficacy remains unclear. This study aimed to analyze the effectiveness of CAZ based on the number of prior ARPIs administered before CAZ treatment.

A retrospective review was conducted on mCRPC patients who received CAZ. The differences in CAZ efficacy based on the number of prior ARPIs were evaluated and prognostic factors for prostate-specific antigen (PSA) progression-free survival (PFS) and OS were analyzed.

A total of 59 patients were categorized into three groups: 12 patients with no prior ARPI, 26 with one prior ARPI, and 21 with two or more prior ARPIs. The median number of CAZ cycles and relative dose intensity were 5% and 60%, respectively. No significant differences were observed in PSA response or PFS among the three groups. Although OS from the first CAZ administration did not significantly differ among the groups, the OS from mCRPC diagnosis was shorter in the group with no prior ARPI. Multivariate analysis identified a time to mCRPC diagnosis of less than 11 months and low serum hemoglobin levels before CAZ administration as significant prognostic factors of poor OS following CAZ treatment.

PSA response, PFS, and OS after CAZ administration did not significantly differ based on the number of prior ARPIs. CAZ efficacy appears consistent regardless of the number of prior ARPI sequences.

The use of poly(ADP-ribose) polymerase inhibitors (PARPi) revolutionized the treatment of BRCA-mutated cancers. Identifying patients exhibiting homologous recombination deficiency (HRD) has been proved useful to predict PARPi efficacy. However, obtaining HRD status remains an arduous task due to its evolution over the time. This causes HRD status to become obsolete when obtained from genomic scars, rendering PARPi ineffective for these patients. Only two HRD tests are currently FDA-approved, both based on genomic scars detection and BRCA mutations testing. Nevertheless, new technologies for obtaining an increasingly reliable HRD status continue to evolve. Application of these tests in clinical practice is an additional challenge due to the need for lower costs and shorter time to results delay.In this review, we describe the currently available methods for HRD testing, including the methodologies and corresponding tests for assessing HRD status, and discuss the clinical routine application of these tests and their technical validation.

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

To evaluate evidence on germline and somatic genomic testing for patients with metastatic prostate cancer and provide recommendations.

A systematic review by a multidisciplinary panel with patient representation was conducted. The PubMed database was searched from January 2018 to May 2024. Articles were selected for inclusion if they reported on patients with metastatic prostate cancer who received a germline or somatic genomic test and/or made comparisons between those tests, reported detection rates, prognostic information, or treatment implications.

A total of 1,713 papers were identified in the literature search. After applying the eligibility criteria, 14 remained: eight systematic reviews and six clinical trials.

Patients with metastatic prostate cancer should undergo both germline and somatic DNA sequencing using panel-based assays. These tests can guide the use of poly(ADP-ribose) polymerase inhibitors, which have a survival benefit in metastatic castration-resistant prostate cancer. In addition, germline testing may have screening implications for additional cancers for patients and cascade testing implications for family members. The data supporting when to perform repeat testing and optimal tissue type to use (eg, primary tumor v metastatic biopsy versus circulating tumor DNA [ctDNA] testing) are more limited, but this panel recommends considering retesting in patients whose results were previously negative or uninformative, and to consider either a metastatic biopsy or ctDNA when a significant change in clinical status occurs. Next-generation genomic sequencing findings that are associated with prognostic only (and not predictive) value should not be used to guide treatment outside of a clinical trial.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.