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.

Clonal hematopoiesis (CH) is an age-related expansion of white blood cell (WBC) progenitors linked to risk of hematological malignancy. Patients with cancer have increased CH prevalence compared to healthy populations, but the characteristics and relevance of CH in advanced urological cancers are unknown. We interrogated CH and circulating tumor DNA (ctDNA) in 299 patients with metastatic urothelial or renal cell carcinoma using error-corrected targeted sequencing of matched WBC DNA and plasma cell-free DNA (cfDNA). 73% of patients carried CH variants at ≥0.25% allele frequency, with 13% exhibiting large CH populations marked by variants ≥10%. CH presence, clone size, and genotype did not impact patient survival. However, CH variants frequently affected solid cancer driver genes and were not individually discriminable from ctDNA variants based on cfDNA features including fragment length. In contrast, matched WBC DNA sequencing to ≥25% of cfDNA depth sufficiently resolved CH from ctDNA variants. Serial profiling revealed ctDNA and CH temporal dynamics including treatment-related expansion of PPM1D-mutated CH clones following platinum chemotherapy. Our data reveal the molecular landscape of CH in urological cancers and suggest that CH interferes in clinical ctDNA genotyping. We urge test providers to comprehensively filter CH from ctDNA results using matched WBC sequencing and propose a cost-effective framework for its integration into existing plasma-only assays.

Synthetic lethality (SL) is a breakthrough concept in cancer therapy that describes a scenario in which the simultaneous inactivation of two genes leads to cell death, whereas inactivation of either gene alone does not. The rise of clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated nuclease 9 (Cas9) technology has provided a new tool for exploring this phenomenon, enabling genome editing and screening. This review evaluates the advancements achieved by CRISPR technology in identifying novel therapeutic targets and comprehending the processes of drug resistance using the concept of SL in cancer cells. This review explores the fundamental concept of SL and its application in cancer therapy, highlighting how the CRISPR-Cas9 system functions and how CRISPR-based screening can be leveraged to identify synthetic lethal genes and investigate the mechanisms of drug resistance. We summarize important research in related fields from recent years, demonstrating the role of CRISPR screening in revealing cancer cellular pathways and identifying new drug targets. We also summarize the clinical trials of related drugs currently underway, and anticipate that with the continuous development of CRISPR technology, its integration with cancer genetics and immuno-oncology will bring new hope to patients with drug-resistant cancers.

Urological cancers, including prostate, kidney, bladder, testicular, and penile cancers, pose a significant health challenge, particularly in their metastatic stages. Surgical interventions remain fundamental, but recent advancements in medical therapies like chemotherapy, immunotherapy, and targeted therapies have shown promise in improving patient outcomes.

This review aims to explore the current landscape of targeted therapies in urological cancers, focusing on the role of key signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), mechanistic (mammalian) target of rapamycin (mTOR), growth factor-related mechanisms, c-Mesenchymal-epithelial transition factor (c-Met)/ hepatocyte growth factor (HGF), programmed cell death protein 1 and its ligand programmed death-ligand 1 (PD-1/PD-L1), and steroid hormone receptor pathways in tumor progression and therapeutic resistance. Key scientific concepts of review Dysregulation of pathways like PI3K/Akt and mTOR contributes to tumorigenesis, metastasis, and resistance to treatment, underscoring their relevance as therapeutic targets. Tyrosine kinase inhibitors and immune checkpoint inhibitors have demonstrated efficacy but face challenges such as intrinsic resistance and treatment-related toxicities. Integrating insights from signaling pathway research with clinical practice holds potential for developing more effective treatment paradigms, enhancing the efficacy of targeted therapies, and improving survival rates for patients with urological cancers.

Metastatic castration-resistant prostate cancer (mCRPC) presents a challenge for clinicians in determining the optimal treatment sequence because of the lack of direct head-to-head comparisons, which is further complicated by the now-widespread use of androgen receptor pathway inhibitors (ARPIs) in metastatic hormone-sensitive prostate cancer (mHSPC).

This study is a Bayesian network meta-analysis (NMA) intended to provide a comprehensive evaluation and comparison of the efficacy of mCRPC treatments across different treatment lines.

We performed a systematic search of ClinicalTrials.gov, extracted information, assessed the risk of bias, and reconstructed missing outcomes. We performed an NMA to evaluate treatment efficacy for overall survival (OS) and progression-free survival (PFS) in first and subsequent lines. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) NMA guidelines and was registered with PROSPERO (CRD42024499607).

The NMA included 43 trials with 33,494 patients. ARPI-based therapies, particularly in combination with poly(ADP-ribose) polymerase inhibitors, demonstrated the most significant benefits for OS and PFS in first-line mCRPC treatment, followed by chemotherapy regimens. However, ARPI re-treatment showed limited effectiveness in subsequent lines, leading to weaker OS and PFS benefits.

This NMA highlights the superiority of ARPI-based therapies and chemotherapies as first-line options for mCRPC while emphasizing the need for treatment class switching after ARPI failure. To refine treatment sequencing and enable precision care, future research should integrate individual participant data to better address patient-level heterogeneity and identify biomarkers for personalized therapy.

Advanced prostate cancer (PCa) is enriched for alterations in DNA damage repair genes; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of drugs that have demonstrated effectiveness in PCa, particularly in tumors with alterations in BRCA1/2 and other homologous recombination repair (HRR) genes, acting through a synthetic lethal mechanism. To prevent or delay drug resistance, and to expand the patient population that can benefit from this class of drug, combination treatment strategies have been developed in preclinical and clinical studies.

This review examines the latest developments in clinical trials testing PARPi for advanced PCa and their emerging role in earlier disease settings. Furthermore, it discusses the critical role of careful patient selection and identification of additional biomarkers to enhance treatment efficacy.

Two PARPi (olaparib and rucaparib) have been approved as monotherapy in metastatic castration-resistant PCa, thereby establishing the first biomarker-guided drug indications in PCa. Several combinations of PARPi with androgen receptor pathway inhibitors have now also been approved. Anemia and fatigue are the main adverse events associated with this drug class in clinical trials; gastrointestinal toxicities are common but usually manageble.

PARPi are active against PCa with HRR mutations, especially in those with germline or somatic BRCA1/2 mutations.  There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease.

Here, we summarize the results from clinical trials testing different poly (ADP-ribose) polymerase inhibitors (PARPi), a novel targeted drug class, in prostate cancer. Overall, the data from these trials confirm the efficacy of this drug class in those metastatic prostate cancers that show specific gene alterations, such as mutations in the BRCA1/2 genes. Several studies combining PARPi with other standard drugs for prostate cancer suggest that there may be efficacy in larger patient populations, but some of these data still need validation in longer follow-up analyses.

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.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of the anticancer drug olaparib, a CYP3A-substrate, has the potential to reduce PK variability, side effects and financial burden associated with this drug. After establishing adequate pharmacokinetic exposure with boosting in the PROACTIVE-A study, the PROACTIVE-B study is designed to evaluate non-inferiority for both efficacy and toxicity of the boosted therapy compared to the standard monotherapy of olaparib.

The PROACTIVE-B study is a nationwide, multicentre, prospective, randomized, non-inferiority trial. A total of 142 patients (128 patients with BRCA+, high-grade, FIGO III/IV ovarian cancer who receive olaparib as maintenance therapy; 14 patients with other approved indications for olaparib) who start olaparib treatment in line with the drug label will be randomized between the standard monotherapy of olaparib 300 mg twice daily (BID) and the boosted therapy of olaparib 100 mg BID with cobicistat 150 mg BID. The co-primary objectives are tolerability (dose reductions due to toxicity), and efficacy (progression-free survival at 12 months) in the ovarian cancer population. Secondary objectives include health status (EQ-5D-5L), patient satisfaction (Cancer Therapy Satisfaction Questionnaire (CTSQ)), and cost effectiveness using the institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ) and iMTA Medical Consumption Questionnaire (iMCQ).

PK boosting of olaparib is a potentially valuable strategy to reduce the olaparib dose and the variability in olaparib exposure with fewer side effects. Moreover, the lower costs related to the boosted therapy contribute to a durable and accessible anticancer treatment for all patients.

The PROACTIVE study has been published at ClinicalTrials.gov under NCT05078671 on October 14, 2021 and at EudraCT under 2021-004032-28 on August 24, 2021.

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.

For patients with castration-sensitive prostate cancer (mCSPC), treatment intensification with androgen deprivation therapy (ADT) plus new androgen receptor pathway inhibitors (ARPIs) has opened a scenario where no guidance exists to indicate the best treatment after progression to metastatic castration-resistant prostate cancer (mCRPC). Clinical decision-making has become even more complex, with the proven benefit for selected patients of triplet therapy with abiraterone or darolutamide added to the double combination therapy of ADT plus docetaxel. The profile of patients for whom triple therapy would be more beneficial is being defined beyond metastatic disease presentation and volume (eg, poor prognosis features). In October 2023 and October 2024, a panel of eight Spanish medical oncologists with expertise in the management of prostate cancer met to discuss the challenges in treating mCRPC. The scientific evidence was reviewed during this meeting, knowledge and experience were shared, and controversies were discussed until a consensus was reached. This information was collected and turned into a manuscript aimed at helping clinicians determine the optimal treatment sequence after disease progression based on scientific evidence and experts' opinions and consensus. To this end, the profile of mCSPC patients who may have received double or triplet therapy is analyzed, current treatment options are reviewed, and treatment algorithms are proposed. New and expected advancements in this field are also presented.

Over the past few years, treatment for advanced prostate cancer has begun shifting away from a one-size-fits-all approach toward biomarker-based therapies for select groups of patients. This review highlights the role of poly-ADP-ribose-polymerase (PARP) inhibitors in metastatic prostate cancer, emerging strategies to target the androgen receptor (AR), and innovative therapies aimed at cell surface proteins, including radioligand therapies, bispecific T cell engagers, and antibody-drug conjugates. For patients with homologous recombination repair (HRR)-mutated metastatic castration-resistant prostate cancer (CRPC), we favor combining a PARP inhibitor (PARPi) with an AR pathway inhibitor (ARPI), provided they can tolerate a more aggressive treatment strategy. In our opinion, patients with BRCA1 or BRCA2 mutations who are unable to handle combination therapy benefit from PARPi monotherapy. We are enthusiastic about the potential of ongoing clinical trials for new AR-directed therapies, such as AR ligand-directed degraders and CYP11A1 inhibitors, in metastatic CRPC. These treatments are expected to be most beneficial for patients whose cancer continues to rely on AR pathway signaling, suggesting they might also be effective in earlier stages of the disease. Progress in drug development and understanding of protein structures has led to new therapies that target cell surface proteins predominantly found in prostate cancer. We use 177Lu-PSMA-617 for patients with PSMA avid metastatic CRPC who have progressed on an ARPI and a taxane chemotherapy. Additionally, we see promising potential in bispecific T-cell engagers (e.g., STEAP1-CD3 and PSMA-CD3) and novel radioligand therapies, including those utilizing actinium, to target these proteins. These advances show great promise in further enhancing survival for patients with metastatic prostate cancer.

Prostate cancer (PCa) is the second most common cancer worldwide and the fifth leading cause of cancer-related deaths among men. The emergence of metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) exemplifies the complex disease management for PCa. PARP inhibitors (PARPis) are being tested to treat mCRPC in tumors with defective homologous recombination repair (HRR) to address this complexity. However, increasing resistance towards PARPi in HRR-deficient patients and the low percentage of HRR-defective mCRPC patients requires the identification of new genes whose deficiency can be exploited for PARPi treatment. XRCC1 is a DNA repair protein critical in the base excision repair (BER) and single strand break repair (SSBR) pathways. We analyzed PCa patients' cohorts and found that XRCC1 expression varies widely, with many patients showing low XRCC1 expression. We created XRCC1 deficiency in PCa models to examine PARPi sensitivity. XRCC1 loss conferred hypersensitivity to PARPi by promoting the accumulation of DNA double-strand breaks, increasing cell-cycle arrest, and inducing apoptosis. We confirmed that XRCC1 expression correlated with PARPi sensitivity using a doxycycline-inducible system. Therefore, we conclude that XRCC1 expression level predicts response to PARPi, and the clinical utility of PARPi in PCa can extend to low XRCC1 expressing tumors.

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.

Germline Testing (GT) for prostate cancer (PCA) is now central to PCA care and hereditary cancer assessment, with a rising role in PCA screening approaches. Guidelines have significantly expanded to include testing patients with metastatic PCA, advanced PCA or with high-risk features, and for males with or without PCA with a strong family cancer history to identify hereditary cancer syndromes for patients and their families. However, the expansion of GT has overwhelmed genetic counselling programs, necessitating the development and evaluation of alternate genetic delivery models. Furthermore, disparities in engagement in PCA GT are of major concern for impacting PCA-related and overall cancer-related outcomes for patients and their families. This review focuses on integrating PCA GT guidelines with implementation strategies and addressing PCA GT disparities to help inform current and future strategies to enhance the benefits of GT across populations.

Selection of patients harboring mutations in homologous recombination repair (HRR) genes for treatment with a PARP inhibitor (PARPi) is challenging in metastatic castration-resistant prostate cancer (mCRPC). To gain further insight, we quantitatively assessed the differential efficacy of PARPi therapy among patients with mCRPC and different HRR gene mutations.

This living meta-analysis (LMA) was conducted using the Living Interactive Evidence synthesis framework. We included clinical trials assessing PARPi as monotherapy in pretreated mCRPC or in combination with an androgen receptor pathway inhibitor (ARPI) in treatment-naïve patients. Random-effects meta-analyses were performed for a priori subgroups stratified by HRR status, BRCA status, and each gene.

This first report for our LMA includes 13 trials (4278 patients). Among patients with pretreated mCRPC receiving PARPi monotherapy, the tumor response rate per 100 person-months was numerically higher for patients with BRCA2 (50% prostate-specific antigen response [PSA50%] 3.3; objective response rate [ORR] 3.3), BRCA1 (PSA50% 1.2; ORR 2.0), or PALB2 (PSA50% 3.3; ORR 1.4) alterations than for patients with ATM (PSA50% 0.4; ORR 0.3), CDK12 (PSA50% 0.2; ORR 0.2), or CHEK2 (PSA50% 1.0; ORR 0.7) alterations. Among patients receiving PARPi + ARPI, a significant radiographic progression-free survival benefit was observed in those with BRCA (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.13-0.62) or CDK12 (HR 0.58, 95% CI 0.35-0.95) alterations, but not in patients with PALB2 (HR 0.53, 95% CI 0.21-1.32), ATM (HR 0.93, 95% CI 0.57-1.53), or CHEK2 (HR 0.92, 95% CI 0.53-1.61) alterations. An overall survival benefit was observed for patients with BRCA alterations (HR 0.47, 95% CI 0.31-0.71) after adjustment for crossover and subsequent therapy, but not for patients with PALB2 (HR 0.33, 95% CI 0.10-1.16), ATM (HR 0.97, 95% CI 0.57-1.67), CDK12 (HR 0.80, 95% CI 0.36-1.78), or CHEK2 (HR 0.81, 95% CI 0.37-1.75) alterations.

Our LMA delivers information on the effect of PARPi therapy in relation to specific gene alterations in mCRPC via an interactive web platform. The evidence suggests the greatest PARPi benefit in patients with BRCA alterations, a strong signal of benefit in patients with PALB2 or CDK12 alterations, and no benefit in patients with ATM or CHEK2 alterations.

Air pollution is associated with various illnesses including cancers, of which prostate cancer is one of the most prevalent malignancies in men. Emerging evidence has suggested that air pollution is a potential risk factor for prostate cancer. This study aimed to explore the relationship between air pollution and prostate cancer in a Taiwanese population. Using data from the Kaohsiung Medical University Hospital Database, we conducted a case-control study to identify patients with prostate cancer, and matched them by age with individuals without prostate cancer. Environmental pollution indices including particulate matter (PM), nitrogen oxides (NOx), sulfur dioxide (SO2), ozone (O3) and carbon monoxide (CO) were correlated with the patients' addresses using data from the Taiwan Central Air Quality Monitoring Network. The analysis included 3541 prostate cancer patients and 7082 age-matched controls. After adjusting for confounders, conditional logistic regression analysis demonstrated significant associations of prostate cancer with PM2.5 (odds ratio [95% confidence interval]: 1.240 [1.134-1.356]) and CO (odds ratio [95% confidence interval]: 1.105 [1.025-1.192]) at the index date, with similar associations observed for average exposure levels over 1, 2, 3, and 5 years prior to the index date. Furthermore, sensitivity analyses revealed that the odds ratios for combined-risk Z-score exposure at the index date and over these same time periods were 1.029, 1.033, 1.034, 1.034, and 1.033, respectively. These findings suggest that prolonged exposure to multiple air pollutants collectively contributes to prostate cancer risk. Further investigations are needed to validate these findings and explore potential underlying mechanisms.

PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effectiveness. This review provides an overview of the current understanding of resistance mechanisms to PARP inhibitors and explores strategies to overcome these challenges. We discuss the basis of synthetic lethality induced by PARP inhibitors and detail diverse resistance mechanisms affecting PARP inhibitors, including homologous recombination restoration, reduced PARP trapping, enhanced drug efflux, and replication fork stabilization. The review then considers clinical approaches to combat resistance, focusing on combination therapies with immune checkpoint inhibitors, DNA damage response inhibitors, and epigenetic drugs. We also highlight ongoing clinical trials and potential biomarkers for predicting treatment response and resistance. The review concludes by outlining future research directions, emphasizing the need for longitudinal studies, advanced resistance monitoring technologies, and the development of novel combination strategies. By tackling PARP inhibitor resistance, this review seeks to aid in the development of more effective cancer therapies, with the potential to improve outcomes for patients with homologous recombination-deficient tumors.

The prostate-specific membrane antigen (PSMA)-targeted radioligand [¹⁷⁷Lu]Lu-PSMA-617 is a new standard treatment for metastatic castration-resistant prostate cancer (mCRPC), but predictive genomic biomarkers informing its rational use are unknown. We performed detailed dissection of prostate cancer driver genes across 290 serial plasma cell-free DNA samples from 180 molecular imaging-selected patients with mCRPC from the randomized TheraP trial of [¹⁷⁷Lu]Lu-PSMA-617 (n = 97) versus cabazitaxel chemotherapy (n = 83). The primary endpoint was PSA50 biochemical response, with secondary endpoints of progression-free survival (PFS) and overall survival (OS). In this post-hoc biomarker analysis, a low pretreatment circulating tumor DNA (ctDNA) fraction predicted a superior biochemical response (100% versus 58%, P = 0.0067) and PFS (median 14.7 versus 6.0 months; hazard ratio 0.12, P = 2.5 × 10-4) on [¹⁷⁷Lu]Lu-PSMA-617 independent of predictive PSMA-positron emission tomography imaging parameters, although this benefit did not extend to OS. Deleterious PTEN alterations were associated with worse PFS and OS on cabazitaxel, whereas ATM defects were observed in select patients with favorable [¹⁷⁷Lu]Lu-PSMA-617 outcomes. Comparing pretreatment and progression ctDNA revealed population flux but no evidence that alterations in individual mCRPC genes (or FOLH1) are dominant causes of acquired [¹⁷⁷Lu]Lu-PSMA-617 or cabazitaxel resistance. Our results nominate new candidate biomarkers for [¹⁷⁷Lu]Lu-PSMA-617 selection and ultimately expand the mCRPC predictive biomarker repertoire. We anticipate our ctDNA fraction-aware analytical framework will aid future precision management strategies for [¹⁷⁷Lu]Lu-PSMA-617 and other PSMA-targeted therapeutics. ClinicalTrials.gov identifier: NCT03392428 .

Our aim was to determine whether induction chemotherapy followed by PARP inhibitor (PARPi) maintenance improves outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring alterations in homologous recombination repair (HRR) genes in comparison to a historical control cohort treated with PARPi monotherapy.

This single-arm, open-label, investigator-initiated phase 2 trial (NCT02985021) enrolled 18 patients with mCRPC with pathogenic alterations in HRR genes between 2018 and 2021 at a single center. Patients received four cycles of induction chemotherapy with docetaxel (60 mg/m2) and carboplatin (area under the curve 5) every 21 d, followed by maintenance rucaparib (600 mg twice daily) until progression or unacceptable toxicity. The primary outcome was radiographic progression-free survival (rPFS). Subsequent to study inception, multiple other studies reported alterations in genes of the BRCA complex (BRCA-C: BRCA1, BRCA2, PALB2) as most predictive of PARPi response; therefore, a post hoc analysis comparing patients with alterations in BRCA-C genes to a historical control cohort was performed.

After median follow-up of 40.3 mo (interquartile range 38.5-not reached [NR]), the median rPFS for all patients was 8.1 mo (95% confidence interval [CI] 6.5-31.2), similar to a historical control cohort treated with PARPi monotherapy. Among the 12 patients with BRCA-C alterations, median rPFS was 17.7 mo (95% CI 7.5-NR; p = 0.05). A key limitation is the single-arm design.

Induction platinum-based chemotherapy followed by maintenance PARPi therapy did not improve outcomes for patients with mCRPC broadly selected for HRR deficiency. However, results were promising in the more stringently selected group with BRCA-C gene alterations. Further studies comparing this approach to PARPi monotherapy are warranted.

de novo low-volume metastatic hormone-sensitive prostate cancer (mHSPC) patients are characterized by a limited number of metastases at diagnosis. Intensifying the current diagnostic and therapeutic approach including multimodality therapy seems to be key in the clinical management of such patients.

We comprehensively review the current staging and treatment options for de novo low-volume mHSPC.

PSMA-PET should be used in staging high-risk prostate cancer to detect metastatic disease and better stratify patients for individualized treatment. In the era of Androgen Receptor Pathway Inhibitors (ARPIs), Androgen Deprivation Therapy (ADT) alone should be considered an undertreatment for the majority of the patients. Based on current data in the literature, the most effective therapeutic strategy seems to be the combination of intensified systemic treatment (including ADT + ARPI) and radiotherapy for the primary tumor. The role of cytoreductive radical prostatectomy is currently being investigated as well as metastasis-directed therapy to metastatic sites.

Prostate cancer is the second most commonly diagnosed cancer and the fifth leading cause of death among men worldwide. Androgen deprivation therapy is a common prostate cancer treatment, but its efficacy is often hindered by the development of resistance, which results in reducing survival benefits. Immunotherapy showed great promise in treating solid tumours; however, clinically significant improvements have not been demonstrated for patients with prostate cancer, highlighting specific drawbacks of this therapeutic modality. Hence, exploring novel strategies to synergistically enhance the efficacy of prostate cancer immunotherapy is imperative. Clinical investigations have focused on the combined use of targeted or gene therapy and immunotherapy for prostate cancer. Notably, tumour-specific antigens and inflammatory mediators are released from tumour cells after targeted or gene therapy, and the recruitment and infiltration of immune cells, including CD8+ T cells and natural killer cells activated by immunotherapy, are further augmented, markedly improving the efficacy and prognosis of prostate cancer. Thus, immunotherapy, targeted therapy and gene therapy could have reciprocal synergistic effects in prostate cancer in combination, resulting in a proposed synergistic model encompassing these three therapeutic modalities, presenting novel potential treatment strategies for prostate cancer.

Approximately 25.0% of metastatic prostate cancer patients harbour DNA damage repair mutations, including BRCA1 and BRCA2, which are actionable targets for poly(ADP-ribose) polymerase (PARP) inhibitors. Accurate detection of BRCA1/2 mutations is critical for guiding targeted therapies, but crucial pre-analytical factors, such as tissue storage duration and DNA fragmentation, drastically affect the reliability of next-generation sequencing (NGS) using real-world diagnostic specimens.

This multicentre study analysed 954 formalin-fixed paraffin-embedded tissue samples from 11 centres, including 559 biopsies and 395 surgical specimens. This study examined the impact of storage duration (<1 year, 1-2 years, and >2 years) and DNA parameters (concentration and fragmentation index) on NGS success rates. Logistic regression and Cox regression analyses were used to assess correlations between these factors and sequencing outcomes.

NGS success rates decreased significantly with longer storage, from 87.8% (<1 year) to 69.1% (>2 years). Samples with higher DNA concentrations and fragmentation indexes had higher success rates (p < 0.001). Surgical specimens had superior success rates (83.3%) compared with biopsies (72.8%) due to better DNA quality. The DNA degradation rate was more pronounced in older samples, underscoring the negative impact of extended storage.

Timely testing of BRCA1/2 mutations is critical for optimizing the identification of prostate cancer patients eligible for PARP inhibitors. Surgical specimens provide more reliable results than biopsies and minimizing the storage duration significantly enhances testing outcomes. Standardizing pre-analytical and laboratory procedures across centres is essential to ensure personalized treatments and improve patient outcomes.

Induction of apoptosis is an important strategy for the treatment of prostate cancer. DR5 is a member of the death receptor superfamily and targeting DR5 is an effective way to induce apoptosis. Pyripyropene O is a natural compound isolated from the marine fungus Aspergillus fumigatus SCSIO 41220. We found it has anti-prostate cancer potential by inducing apoptosis; Methods: The effects of pyripyropene O on the viability, proliferation, cell cycle, apoptosis and migration of prostate cancer cells were investigated by MTT assay, plate clone formation assay, 3D cell sphere assay, flow cytometry and real-time cell analysis. Transmission electron microscopy was used to observe the changes in the internal structure of prostate cancer cells after treatment with pyripyropene O. After determining the mode of cell death, the mechanism of action of pyripyropene O on prostate cancer was further investigated using apoptotic protein microarray, western blot, qPCR, molecular docking, cellular immunofluorescence staining and cellular thermal shift assay. After explaining the mechanism of action of pyriproxyfen O, the in vivo absorption, distribution, metabolism, excretion and potential toxicity of pyriproxyfen O were investigated using ADMETLab 2.0 software. Finally, a zebrafish xenograft tumour model was developed to evaluate the anti-prostate cancer effects of pyriproxyfen O in vivo; Results: The experimental results at the cellular level showed that pyripyropene O inhibited the survival, proliferation and migration of prostate cancer cells, and also showed that pyripyropene O blocked the prostate cancer cell cycle at the G2/M phase and induced apoptosis. At the molecular level, pyripyropene O binds to the transcription factor YY1, promotes YY1 nuclear translocation, regulates the transcription level of DR5, a target gene of YY1, and upregulates the expression of DR5 mRNA and protein. The in vivo results showed that pyripyropene O effectively inhibited the development of prostate cancer in zebrafish; Conclusions: Pyripyropene O has a clear anti-prostate cancer effect at both cellular and animal levels, inhibiting the survival and proliferation of prostate cancer cells by binding to the transcription factor YY1 to activate the expression of DR5 to promote apoptosis, thus exerting an inhibitory effect on prostate cancer.

Bone metastases represent a critical complication in oncology, frequently indicating advanced malignancy and substantially reducing patient quality of life. This review provides a comprehensive analysis of the complex interactions between tumor cells and the bone microenvironment, emphasizing the relevance of the "seed and soil" hypothesis, the RANK/RANKL/OPG signaling axis, and Wnt signaling pathways that collectively drive metastatic progression. The molecular and cellular mechanisms underlying the formation of osteolytic and osteoblastic lesions are examined in detail, with a particular focus on their implications for bone metastases associated with breast, prostate, lung, and other cancers. A central component of this review is the categorization of pathological biomarkers into four types: diagnostic, prognostic, predictive, and monitoring. We provide a comprehensive evaluation of circulating tumor cells (CTCs), bone turnover markers (such as TRACP-5b and CTX), advanced imaging biomarkers (including PET/CT and MRI), and novel genomic signatures. These biomarkers offer valuable insights for early detection, enhanced risk stratification, and optimized therapeutic decision-making. Furthermore, emerging strategies in immunotherapy and bone-targeted treatments are discussed, highlighting the potential of biomarker-guided precision medicine to enhance personalized patient care. The distinctiveness of this review lies in its integrative approach, combining fundamental pathophysiological insights with the latest developments in biomarker discovery and therapeutic innovation. By synthesizing evidence across various cancer types and biomarker categories, we provide a cohesive framework aimed at advancing both the scientific understanding and clinical management of bone metastases.

Recent advancements in the understanding of the genetic background of genitourinary cancers allowed for a successful introduction of targeted antitumor agents to prostate cancer (PCa) treatment. Inhibitors of the poly ADP-ribose polymerase enzyme (PARPi) transformed the treatment landscape of metastatic prostate cancer, and being increasingly studied in earlier disease stages. However, they are associated with nonnegligible toxicity, therefore, we aimed to summarize their side-effect profile in patients with PCa.

Hematologic toxicities, particularly anemia, thrombocytopenia, and neutropenia are among the most common and serious adverse events associated with PARPi, highlighting the need for regular blood count monitoring. Nonhematologic side effects, including fatigue, nausea, vomiting, diarrhea, and constipation, are common, and can be mitigated with supportive interventions like dietary modifications, antiemetics, or stool management techniques. Special attention should be given to patients with therapy-resistant or persistent cytopenia, in whom bone marrow biopsy should be considered, as it can indicate myelodysplastic syndrome and acute myeloid leukemia.

PARP inhibitors represent a major advancement in the management of metastatic prostate cancer, offering a significant survival benefit in applicable cases. However, patients need to be carefully selected and informed, to allow for optimal balancing between the benefits and nonneglectable risks of severe toxicities. Better understanding of PARPi toxicity profile can improve personalized decision-making and enhance treatment compliance, through raising patients' awareness about the possible side effects of PARPi.

Inhibition of the deubiquitinating enzyme USP1 can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD) and represents a novel therapeutic strategy for the treatment of BRCA1/2-mutant cancers, potentially including patients whose tumors have primary or acquired resistance to PARP inhibitors (PARPi). In this study, we present a comprehensive characterization of TNG348, an allosteric, selective, and reversible inhibitor of USP1. TNG348 induces dose-dependent accumulation of ubiquitinated protein substrates both in vitro and in vivo. CRISPR screens show that TNG348 exerts its antitumor effect by disrupting the translesion synthesis pathway of DNA damage tolerance through RAD18-dependent ubiquitinated PCNA. Although TNG348 and PARPi share the ability to selectively kill HRD tumor cells, CRISPR screens reveal that TNG348 and PARPi do so through discrete mechanisms. Particularly, knocking out PARP1 causes resistance to PARPi but sensitizes cells to TNG348 treatment. Consistent with these findings, combination of TNG348 with PARPi leads to synergistic antitumor effects in HRD tumors, resulting in tumor growth inhibition and regression in multiple mouse xenograft tumor models. Importantly, our data on human cancer models further show that the addition of TNG348 to PARPi treatment can overcome acquired PARPi resistance in vivo. Although the clinical development of TNG348 has been discontinued because of unexpected liver toxicity in patients (NCT06065059), the present data provide preclinical and mechanistic support for the continued exploration of USP1 as a drug target for the treatment of patients with BRCA1/2-mutant or HRD cancers.

To provide evidence-based recommendations for patients with metastatic castration-resistant prostate cancer (mCRPC).

An Expert Panel including patient representation completed a systematic review of the evidence and made recommendations.

Depending upon prior treatment received, androgen receptor pathway inhibitors (ARPIs: enzalutamide, abiraterone with prednisone), poly(ADP-ribose) polymerase inhibitors (PARPi), chemotherapeutic agents (docetaxel, cabazitaxel), radiopharmaceuticals (radium 223, 177Lu-prostate-specific membrane antigen [PSMA]-617), and sipuleucel-T have demonstrated an overall survival (OS) benefit for patients with mCRPC. For patients with BRCA1/2 alterations who did not receive prior ARPI, the combination of PARPi and ARPI (talazoparib + enzalutamide, olaparib and/or niraparib + abiraterone) has shown clinical benefit. For patients with BRCA1/2 alterations who received prior ARPI or ARPI followed by docetaxel, olaparib showed OS benefit. In select patients with microsatellite instability-high/mismatch repair-deficient, pembrolizumab showed clinical efficacy.

Prior systemic therapy for castration-sensitive prostate cancer will determine subsequent therapy used for mCRPC. Continue androgen-deprivation therapy for patients with mCRPC indefinitely. Early adoption of somatic genetic testing and palliative care is recommended. Patients with mCRPC and bony metastases should receive a bone-protective agent. The panel recommends the combination of ARPI with PARPi in patients with BRCA1/2 alterations who did not receive prior ARPI. For patients who received prior ARPI, the panel recommends docetaxel chemotherapy. The panel recommends 177Lu-PSMA-617 or cabazitaxel chemotherapy for patients who receive prior ARPI and docetaxel chemotherapy. For patients with BRCA1/2 alterations who received prior ARPI, the panel recommends PARPi monotherapy. Radium 223 is recommended for patients with symptomatic bone-only disease. Evidence for optimal sequencing for mCRPC regimens is lacking.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Poly (ADP-ribose) polymerase (PARP) inhibitors have improved the prognosis of homologous recombination deficient (HRD) ovarian cancer (OC), while effective therapeutic strategies for HR-proficient (HRP) OC still need to be established. This study investigates senescence-mediated inflammation as a novel mechanism of action for PARP inhibitors in HRP cancers. Transcriptome analyses were performed in olaparib-treated HeLa cells as a HRP model. Interferon regulatory factor-Lucia luciferase (IRF-Luc) reporter activity was assessed. The effects of PARP inhibitors on senescence-like phenotypes were assessed in seven HRP cancer cell lines, based on morphological changes, senescence-associated β-galactosidase (SA-β-GAL) activity, cellular granularity, and senescence-associated secretory phenotype (SASP)-related gene expression. Peripheral blood mononuclear cell (PBMC) migration assays were also performed with the conditioned medium in treatment with the PARP inhibitor. Transcriptome analyses revealed numbers of inflammatory cytokine- and chemokine-related pathways were significantly upregulated in olaparib-treated HeLa cells, which were confirmed by IRF-Luc reporter assays. The PARP inhibitors induced senescent phenotypes in HRP cancer cell lines: flattened and enlarged morphology, increased SA-β-GAL activity, elevated cellular granularity, and upregulated expressions of SASP-related genes (e.g., IL1B, IL6, and CXCL10). Furthermore, in vitro migration assays revealed that PARP inhibitor-treated HRP cancer cells attracted PBMCs more abundantly, suggesting the potential for recruiting immune cells to HRP cancer cells through senescence-mediated immunological activation. Our findings suggest that PARP inhibitors recruit immune cells to HRP cancer cells, potentially activating immune responses in the tumor microenvironment, providing new insights into the clinical benefits of PARP inhibitors in immunotherapy for patients with HRP OC.

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.

High-throughput genomic analyses are being implemented in clinical practice. MODIFY is a retrospective study of the first introduction of genomic profiling and molecular tumor boards in the country of Luxembourg. The primary objective was to assess whether patients derived a clinical benefit by measuring the percentage of patients who presented a progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than PFS on previous therapy (PFS1). A total of 94 patients were included. In total, 45 patients (53.57% of patients with successful next-generation sequencing [NGS] analysis) were found to have an actionable mutation. Of these, 11 patients received the treatment recommended by the molecular tumor board, another 12 received best-supportive care, and 20 were treated with conventional therapy. PFS2 and PFS1 data were available for eight patients. The PFS2/PFS1 ratio was ≥ -1.3 in 62.5% (n = 5/8; CI [30.38, 86.51]) of patients; three patients showed a partial response, and median overall survival (OS) was 7.3 months. Although the examined population was small, this study further supports evidence indicating that patients with advanced cancer benefit from molecular profiling and targeted therapy.

This study aims to assess the potential cost-effectiveness of using whole-genome sequencing (WGS)-guided systemic therapy in metastatic castrate-resistant prostate cancer compared with the European Association of Urology guideline recommended diagnostics from a Dutch societal perspective.

A decision analytic model combining a decision tree and partitioned survival models was developed to link diagnostic results with subsequent biomarker-guided treatments. Two diagnostic strategies, WGS and guideline-recommended practice-the genomic testing for breast cancer gene 1/2 (BRCA1/2) and deficient mismatch repair, were simulated to compare the health outcome and cost. Treatment effectiveness was estimated through survival analysis using published trial data. Sensitivity and scenario analyses were conducted to examine result robustness and to identify conditions under which WGS may be cost-effective.

WGS identified an additional 21% of patients eligible for personalized therapy (PD-1/PDL-1 inhibitors and olaparib), resulting in an incremental increase in cost (€14 260) and quality-adjusted life years (QALY = 0.05). These results yielded an incremental cost-effectiveness ratio of €289 625 per QALY gained. WGS would become cost-effective if the cost of biomarker-guided therapies decreases by 62% and when identifying a proportion of 23% more patients with actional targets.

Our findings suggest that future treatments with improved efficacy and reduced cost could potentially make the WGS strategy cost-effective. Its unaccounted potential value to identify prognostic biomarkers, diagnostic alternatives, and patient heterogeneity should be addressed in future research and considered for optimal implementation. New reimbursement options are needed considering the high prices of biomarker-guided therapies that drive the incremental cost-effectiveness ratio.

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.