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.

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.

Contemporary advances in prostate cancer treatments have markedly improved patient outcomes, yet concerns persist regarding the increased cardiovascular toxicity of prostate cancer treatments, which is multifaceted. Local therapies entail non-negligible cardiovascular risks. The effects of androgen deprivation therapy, which is pivotal in disease management, on cardiovascular health remains contentious, with gonadotropin-releasing hormone agonists and antagonists showing varying cardiovascular outcomes. Despite the ongoing controversy over the cardiovascular risks of gonadotropin-releasing hormone antagonists versus agonists, current evidence does not support favouring one over the other based solely on cardiovascular risk. Combination therapy with androgen receptor pathway inhibitors and androgen deprivation therapy shows additive cardiovascular risks, but robust comparative data are lacking. Chemotherapies such as docetaxel and cabazitaxel, along with emerging targeted therapies and radiopharmaceuticals, are associated with varied cardiovascular risks, necessitating personalized patient assessment. Clinicians should adhere to cardio-oncology guidelines when prescribing therapeutic agents, especially for patients with pre-existing cardiovascular conditions. Optimal monitoring and management strategies are essential to mitigate cardiovascular morbidity and mortality.

This review is intended to reflect the currently available literature on both clinically significant germline mutations in DNA damage repair (DDR) genes as well as the importance of ancestral diversity in the pathogenesis of prostate cancer (PCa). The second most prevalent cancer worldwide in men is PCa, causing significant morbidity and mortality in its advanced stage. Emerging data highlight the substantial role of germline mutations of DDR genes in PCa pathogenesis, especially in progression to aggressive forms of the disease. Germline genetic testing is recognized as a necessary tool for efficient, individualized patient care. NCCR guidelines recommend inquiring about the family history of PCa and known germline variants and, if indicated, proceeding with germline multigene testing followed by post-test genetic counseling. Depending on the germline mutations in HR repair genes or in MMR genes, specific treatment options may provide clinical benefit. We will discuss specific germline mutations that are involved in PCa progression and prognosis in racially diverse populations.

Prostate cancer (PCa) is one of the most common cancers in men, and cyclin-dependent kinase 12 (CDK12) is emerging as a novel star player in the PCa tumorigenesis and progression to castration-resistant prostate cancer (CRPC). In PCa, CDK12 alterations are mostly loss-of-function mutations featuring intronic polyadenylation (IPA), focal tandem duplications (FTDs), and R-loops formation and transcription-replication conflicts (TRCs). The occurrence of IPA can result in homologous recombination deficiency (HRD) and androgen receptor (AR) variation. FTDs induce neoantigens and increase the expression of the AR, MYC, and other hotspot- associated genes. R-loops lead to TRCs and influence various cellular processes, including gene expression and genome stability. Due to the poor prognosis of CDK12-mutant PCa patients and the mediocre response to classic standard therapies, HRD and increased neoantigen levels have provided clinicians with new insights into alternative systematic treatments for this novel PCa phenotype. In this review, we summarize the roles of CDK12 mutations in PCa and discuss their clinical value, suggesting that CDK12 potentially represents a target for further research and the development of clinical strategies for PCa.

PARP inhibitor (PARPi) treatment is an effective option for patients with metastatic castration-resistant prostate cancer (mCRPC). There are few data on the cardiovascular and thromboembolic safety of these agents in mCRPC, as cardiovascular and thromboembolic adverse events (AEs) are uncommon. Our aim was to analyze the incidence and risk of major adverse cardiovascular events (MACEs), thromboembolic events, and hypertension with PARPi therapy in mCRPC.

We conducted a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We systematically searched the PubMed, EMBASE, and Cochrane databases and the American Society of Clinical Oncology and European Society of Medical Oncology meeting abstracts for clinical trials on PARPi use in mCRPC up to March 31, 2024. We analyzed the pooled incidence of all-grade and high-grade MACEs, thromboembolic events, and hypertension, and calculated risk ratios (RRs) for PARPi versus non-PARPi treatment.

We included 11 phase 2 or 3 trials in our meta-analysis. Hypertension was the most common AE for both any-grade (17.2%) and high-grade (9.3%) events. In comparison to other treatments, PARPi was associated with significantly higher risk of high-grade MACEs (RR 2.03; p = 0.03) and thromboembolic events (RR 2.15; p = 0.002), especially venous thromboembolism (VTE; RR 2.13; p = 0.004) and pulmonary embolism (RR 3.60; p = 0.001). The risk of hypertension, any-grade MACEs, and thromboembolic AEs was not significantly higher, apart from VTE (RR 2.17; p = 0.01).

There is higher risk of high-grade cardiovascular and thromboembolic toxicity with PARPi use in comparison to other treatments in mCRPC, although these toxicities are rare. Clinicians should be aware of this risk, especially in a population that often has comorbidities and concomitant treatments, for correct monitoring and management of these AEs.

Drugs called PARP inhibitors are very effective in the treatment of metastatic prostate cancer that does not respond to hormone treatment. However, their use is associated with some cardiovascular adverse events, although these are rare. Our study shows that these events seem to be more frequent with PARP inhibitors than with other treatments, especially for severe grades. Doctors and patients should be aware of this risk to help in preventing, recognizing, and managing the occurrence of these rare complications.

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.

The ubiquitin receptor ADRM1/Rpn13 governs the specificity of eukaryotic protein degradation. We first discovered a novel spliced variant of ADRM1 with a skipped exon 9, termed ADRM1-ΔEx9, in human hepatocellular carcinoma (HCC) by SMRT sequencing. This study aimed to elucidate this novel ubiquitin receptor's underlying biology and clinical implications in HCC.

The role of ADRM1-ΔEx9 in early liver carcinogenesis was studied using human liver-derived non-tumoral organoids and a murine model with hydrodynamic in vivo transfection. ADRM1-ΔEx9 biology in HCC and its potential as a biomarker for predicting olaparib response were investigated using patient-derived tumor organoids and xenograft models. The underlying mechanism was delineated using the Proteome Profiler Human Ubiquitin Array.

ADRM1-ΔEx9, not its full-length counterpart, conferred human liver organoids with pro-survival advantages and led to more profound tumor formation in a hydrodynamic transfected murine model. Functional knockdown resulted in spontaneous apoptosis in cell lines and patient-derived organoids, highlighting a pivotal role for ADRM1-ΔEx9 in HCC oncogenicity. Mechanistically, the shortened C-terminus of ADRM1-ΔEx9 interacted with a different deubiquitinase partner (BAP1) to alter proteasome specificity. The new exon 8-10 fusion in ADRM1-ΔEx9 creates a de novo binding site for the tumor suppressor protein FBXW7, resulting in its selective proteasome-mediated degradation. The loss of FBXW7 protein in ADRM1-ΔEx9-expressing tumors underscores their sensitivity to the PARP inhibitor olaparib. Notably, findings on ADRM1-ΔEx9 in primary HCC tumors denote its overexpression in a subgroup of patients with inferior survival and a window of therapeutic opportunity through a synthetic lethal association with olaparib.

ADRM1-ΔEx9 redirects ubiquitin proteasome specificity to selectively degrade the tumor suppressor protein FBXW7. This promotes HCC tumor formation and provides a synthetic lethal link for PARP inhibitor therapy.

Reduced tumor suppressor protein FBXW7 expression is pivotal in hepatocellular carcinoma (HCC) pathogenesis and other liver diseases. However, the regulatory mechanism governing FBXW7 protein expression remains elusive. Herein, we unveil a non-canonical spliced isoform of the ubiquitin receptor ADRM1 that selectively degrades FBXW7 protein, thereby promoting the premalignant transformation of hepatic cells and conferring growth advantages to HCC tumors. Furthermore, our results demonstrate that ADRM1-ΔEx9-expressing HCC tumors exhibited sensitivity to olaparib in a dose-dependent manner, implicating the potential use of olaparib in targeting ADRM1-ΔEx9-driven HCC growth.

Metastatic prostate cancer remains incurable. Though significant progress has been made in the field, the search for agents that improve outcomes for patients is ongoing. Several clinical trials have explored the benefit of combining PARP inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPIs) for metastatic castrate resistant prostate cancer (mCRPC), especially those cancers with alterations in homologous recombination repair (HRR) genes. Niraparib, a highly selective inhibitor of PARP1 and PARP2, has been shown to confer a radiographic progression-free survival benefit in the treatment of mCRPC with HRR-associated gene alterations, particularly BRCA1 and BRCA2 (BRCA1/2), when combined with abiraterone acetate plus prednisolone (AAP). This combination has recently been approved in the USA, Canada and Europe for patients with mCRPC and a BRCA1/2 gene mutation. This review summarizes the evidence with regards to the pharmacologic activity and clinical efficacy of niraparib with a specific focus on its efficacy in combination with AAP in mCRPC patients with HRR alterations.

PARP inhibitors (PARPi) have received regulatory approval for the treatment of several tumors, including prostate cancer (PCa), and demonstrate remarkable results in the treatment of castration-resistant prostate cancer (CRPC) patients characterized by defects in homologous recombination repair (HRR) genes. Preclinical studies showed that DNA repair genes (DRG) other than HRR genes may have therapeutic value in the context of PARPi. To this end, we performed multiple CRISPR/Cas9 screens in PCa cell lines using a custom sgRNA library targeting DRG combined with PARPi treatment. We identified DNA ligase 1 (LIG1), essential meiotic structure-specific endonuclease 1 (EME1), and Fanconi anemia core complex associated protein 24 (FAAP24) losses as PARPi sensitizers and assessed their frequencies from 3% to 6% among CRPC patients. We showed that concomitant inactivation of LIG1 and PARP induced replication stress and DNA double-strand breaks, ultimately leading to apoptosis. This synthetic lethality (SL) is conserved across multiple tumor types (e.g., lung, breast, and colorectal), and its applicability might be extended to LIG1-functional tumors through a pharmacological combinatorial approach. Importantly, the sensitivity of LIG1-deficient cells to PARPi was confirmed in vivo. Altogether, our results argue for the relevance of determining the status of LIG1 and potentially other non-HRR DRG for CRPC patient stratification and provide evidence to expand their therapeutic options.

The cyclin-dependent kinase (CDK), CDK12, is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer characterized predominantly by frameshift, loss-of-function mutations in CDK12. This subtype exhibits aggressive clinical features.

Using isogenic prostate cancer models generated by CRISPR/Cas9-mediated inactivation of CDK12, we conducted a chemical library screen of ∼1,800 FDA-approved drugs. We inhibited cyclin K and CDK13 and evaluated the effects on PARP inhibitor (PARPi) sensitivity. CDK12 truncation and kinase domain mutations were expressed in cell lines to determine the effects on PARPi sensitivity. Mice bearing control and CDK12-mutant prostate tumors were treated with rucaparib. Finally, we evaluated PSA responses in patients with CDK12 mutations treated with rucaparib on the TRITON2 trial.

Cancer cells lacking CDK12 are more sensitive to PARPi than isogenic wild-type cells, and sensitivity depends on the degree of CDK12 inhibition. Inhibiting cyclin K, but not CDK13, also led to PARPi sensitivity and suppressed homologous recombination. CDK12 truncation mutants remained sensitive to PARPi, whereas kinase domain mutants exhibited intermediate sensitivity. The PARPi rucaparib suppressed tumor growth in mice bearing CDK12-mutated tumors. Finally, 6 of 11 (55%) patients with prostate cancer with biallelic CDK12 mutations had reductions in serum PSA levels when treated with rucaparib on the TRITON2 clinical trial.

In prostate cancer, sensitivity to PARPi is dependent on the specific type and zygosity of the CDK12 mutation. PARPi monotherapy may have some activity in patients with prostate cancer with biallelic inactivating CDK12 alterations.

Homologous recombination repair mutation (HRRm) status may guide risk-stratification and treatment decisions, including polyadenosine diphosphate-ribose polymerase inhibitor use, in advanced prostate cancer. Although HRRm prevalence has been reported in single-institution studies or clinical trials, real-world HRRm prevalence in diverse populations is unknown. We describe HRRm in the clinical setting using two real-world clinicogenomic databases: the Flatiron Health and Foundation Medicine, Inc. Clinico-Genomic Database (CGDB), a national electronic health record-derived database, and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE).

This cross-sectional analysis included 3757 individuals diagnosed with prostate cancer who had next generation sequencing (NGS) as standard of care. The CGDB included men with advanced/metastatic prostate cancer and genetic data included both germline and somatic pathogenic mutations. The GENIE analysis included men with prostate cancer whose received NGS as standard of care, but the data were filtered to include somatic mutations only. Due to key differences among databases, direct comparisons were not possible. Overall prevalence of HRRm was calculated and stratified by demographic and clinical characteristics.

HRRm prevalence (combined germline and somatic) in CGDB (n = 487) was 24.6% (95% CI 20.9-28.7%), with no major differences across demographic and disease characteristic subgroups. HRRm prevalence (somatic) in GENIE (n = 3270) was 11.0% (95% CI 10.0-12.1%), which varied between 9.5% and 18.4% across treatment centers.

Approximately one-quarter of patients with advanced/metastatic prostate cancer in the CGDB had germline and/or somatic HRRm, which is consistent with clinical trials such as the PROfound study that used a similar NGS platform and algorithm to define HRRm. In the GENIE database, HRRm prevalence varied by treatment center or NGS platform. More research is needed to understand real-world HRRm prevalence variations.

Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APSIs) remains ongoing challenges. Here, we present BSJ-5-63, a novel proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multi-pronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained "BRCAness" state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including both in vitro and in vivo CRPC models, demonstrate that BSJ-5-63 exerts potent anti-tumor activity in both AR-positive and AR-negative setting. This study introduces BSJ-5-63 as a promising therapeutic agent that addresses both DNA repair and AR signaling mechanisms, with potential benefits for a board patient population.

The prevalence of cardiovascular risk factors and disease is high in patients with newly diagnosed prostate cancer (PC). Survivorship of PC patients is often determined by cardiovascular disease (CVD). Our review synthesizes the most recent literature exploring the dynamics between PC and CVD across the disease trajectory and treatments. We review key ongoing clinical trials in the field and highlight avenues for future study.

We conducted a comprehensive narrative review of the literature using various search strategies in three databases (PubMed, Web of Science, ClinicalTrials.gov), focusing on literature published between 2000 and 2024.

We discuss the significance of CVD-related mortality in PC, review the risk factors, and highlight potential mechanisms for accelerated CVD in the androgen-deprivation setting. Furthermore, we summarize key literature of CVD and cardiotoxicity for various therapeutic approaches in PC, including orchiectomy, taxane-based chemotherapy, GnRH-axis targets, and next-generation hormonal agents and PARP inhibitors. Lastly, we discuss prevention strategies and the importance of multi-disciplinary care in this setting.

CVD is a major cause of death in men with PC. Various novel therapeutic approaches have been pivotal in improving oncologic outcomes, but emerging data demonstrate a complex interplay between the androgen axis and CVD that is likely affected by modern treatment strategies. Given the prolonged PC survivorship, unraveling non-oncologic related causes of death and investigating prevention strategies are imperative (Fig. 1). Fig. 1 LANDSCAPE OF PROSTATE CANCER.: Spectrum of prostate cancer disease states (red) and interventions (yellow) with the potential role for optimization (green) to improve cardiovascular outcomes in the future (blue).

Despite recent advancements in the treatment of metastatic castrate-resistant prostate cancer (mCRPC), this disease remains lethal. A novel family of targeted pharmaceuticals known as poly-ADP-ribose polymerase (PARP) inhibitors has been developed to treat mCRPC patients with homologous recombination repair (HRR) gene alterations. The FDA recently approved olaparib and rucaparib for treating mCRPC patients with HRR gene alterations. Ongoing trials are investigating combination therapies involving PARP inhibitors combined with radiation, chemotherapy, immunotherapy, and androgen receptor signaling inhibitors (ARSIs) to improve the effectiveness of PARP inhibitors and broaden the range of patients who can benefit from the treatment. This review provides an overview of the development of PARP inhibitors in prostate cancer and analyzes the mechanisms underlying their resistance.

Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.

Olaparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that provides benefit in combination with hormonal therapies in patients with metastatic prostate cancer who harbor homologous recombination repair (HRR) alterations. Its efficacy in the absence of androgen deprivation therapy has not been tested.

To determine the activity of olaparib monotherapy among patients with high-risk biochemically recurrent (BCR) prostate cancer after radical prostatectomy.

This phase 2, single-arm nonrandomized controlled trial enrolled genetically unselected patients across 4 sites in the US from May 2017 to November 2022. Eligible patients had BCR disease following radical prostatectomy, a prostate-specific antigen (PSA) doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher, and a testosterone level of 150 ng/dL or higher.

Treatment was with olaparib, 300 mg, by mouth twice daily until doubling of the baseline PSA, clinical or radiographic progression, or unacceptable toxic effects.

The primary end point was a confirmed 50% or higher decline in PSA from baseline (PSA50). Key secondary end points were outcomes by HRR alteration status, as well as safety and tolerability.

Of the 51 male patients enrolled (mean [SD] age, 63.8 [6.8] years), 13 participants (26%) had a PSA50 response, all within the HRR-positive group (13 of 27 participants [48%]). All 11 participants with BRCA2 alterations experienced a PSA50 response. Common adverse events were fatigue in 32 participants (63%), nausea in 28 (55%), and leukopenia in 22 (43%), and were consistent with known adverse effects of olaparib.

In this nonrandomized controlled trial, olaparib monotherapy led to high and durable PSA50 response rates in patients with BRCA2 alterations. Olaparib warrants further study as a treatment strategy for some patients with BCR prostate cancer but does not have sufficient activity in those without HRR alterations and should not be considered for those patients.

ClinicalTrials.gov Identifier: NCT03047135.

The detection of germline pathogenic variants (gPVs) in BRCA1/2 and other breast cancer (BC) genes is rising exponentially thanks to the advent of multi-gene panel testing. This promising technology, coupled with the availability of specific therapies for BC BRCA-related, has increased the number of patients eligible for genetic testing. Implementing multi-gene panel testing for hereditary BC screening holds promise to maximise benefits for patients at hereditary risk of BC. These benefits range from prevention programs to antineoplastic-targeted therapies. However, the clinical management of these patients is complex and requires guidelines based on recent evidence. Furthermore, applying multi-gene panel testing into clinical practice increases the detection of variants of uncertain significance (VUSs). This augments the complexity of patients' clinical management, becoming an unmet need for medical oncologists. This review aims to collect updated evidence on the most common BC-related genes besides BRCA1/2, from their biological role in BC development to their potential impact in tailoring prevention and treatment strategies.

RAD51C and RAD51D are crucial in homologous recombination (HR) DNA repair. The prevalence of the RAD51C and RAD51D mutations in breast cancer varies across ethnic groups. Associations of RAD51C and RAD51D germline pathogenic variants (GPVs) with breast and ovarian cancer predisposition have been recently reported and are of interest.

We performed multi-gene panel sequencing to study the prevalence of RAD51C and RAD51D germline mutations among 3728 patients with hereditary breast and/or ovarian cancer (HBOC).

We identified 18 pathogenic RAD51C and RAD51D mutation carriers, with a mutation frequency of 0.13% (5/3728) and 0.35% (13/3728), respectively. The most common recurrent mutation was RAD51D c.270_271dupTA; p.(Lys91Ilefs*13), with a mutation frequency of 0.30% (11/3728), which was also commonly identified in Asians. Only four out of six cases (66.7%) of this common mutation tested positive for homologous recombination deficiency (HRD).

Taking the family studies in our registry and tumor molecular pathology together, we concluded that this relatively common RAD51D variant showed incomplete penetrance in our local Chinese community. Personalized genetic counseling emphasizing family history for families with this variant, as suggested at the UK Cancer Genetics Group (UKCGG) Consensus meeting, would also be appropriate in Chinese families.

Prostate cancer is one of the most prevalent malignancies in men. In the United States, 1 in 8 men will be diagnosed with prostate cancer in their lifetime. Specifically, studies have delved into male subgroups that present a heightened risk for prostate cancer. Despite such high prevalence, prostate cancer can be heterogeneous and carry complexities that manifest differently between individuals. Metastatic hormone-sensitive prostate cancer (mHSPC) often has an abbreviated, aggressive disease course, and can have varying presentations with different molecular profiles that determine response/resistance to the approved treatments targeting the androgen-receptor pathway (eg, enzalutamide, apalutamide, darolutamide, and abiraterone acetate). We present a case of mHSPC quickly progressing to mCRPC, found to have microsatellite instability in mCRPC and excellent response to pembrolizumab, which raises the critical issues of early molecular testing and treatments personalized for the individual patient.

Outcomes data for DNA-damaging therapeutics for men with prostate cancer (PC) and non-BRCA1/2 homologous recombination repair (HRR) mutations are limited. We evaluated outcomes by HRR alteration in men with PC treated with poly(ADP-ribose)polymerase inhibitors (PARPi) and/or platinum chemotherapy.

Retrospective data from the PROMISE consortium were used. Clinical outcomes differences were assessed between patients with BRCA1/2 mutations (cohort A) and those with HRR mutations without direct BRCA complex interaction (cohort B: ATM, CDK12, CHEK1, CHEK2, and FANCL). Outcomes in patients with HRR mutations with direct BRCA complex interaction were also explored (cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, and BRIP1).

One hundred and forty-six patients received PARPi (cohort A: 94, cohort B: 45, cohort C: 7) and 104 received platinum chemotherapy (cohort A: 48, cohort B: 44, cohort C: 10). PSA50 response rate to PARPi was higher in cohort A (61%) than cohort B (5%), P < .001. Median clinical/radiographic progression-free survival (crPFS) with PARPi in cohort A was significantly longer than in cohort B: 15.9 versus 8.7 months, P = .005. PSA50 response rate to platinum therapy was higher in cohort A (62%) than in cohort B (32%), P = .024, although crPFS was not significantly different. PSA50 response rate to PARPi and platinum was 40% and 32%, respectively, in cohort C. In multivariable analysis, cohort A had significantly improved overall survival and crPFS compared with cohort B with PARPi but not platinum chemotherapy.

Patients with BRCA1/2-mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.

Testing for homologous recombination deficiency (HRD) mutations is pivotal to assess individual risk, to proact preventive measures in healthy carriers and to tailor treatments for cancer patients. Increasing prominence of poly(ADP-ribose) polymerase (PARP) inhibitors with remarkable impact on molecular-selected patient survival across diverse nosologies, ingrains testing for BRCA genes and beyond in clinical practice. Nevertheless, testing strategies remain a question of debate. While several pathogenic BRCA1/2 gene variants have been described as founder pathogenic mutations frequently found in patients from Russia, other homologous recombination repair (HRR) genes have not been sufficiently explored. In this study, we present real-world data of routine HRR gene testing in Russia.

We evaluated clinical and sequencing data from cancer patients who had germline/somatic next-generation sequencing (NGS) HRR gene testing in Russia (BRCA1/2/ATM/CHEK2, or 15 HRR genes). The primary objectives of this study were to evaluate the frequency of BRCA1/2 and non-BRCA gene mutations in real-world unselected patients from Russia, and to determine whether testing beyond BRCA1/2 is feasible.

Data of 2,032 patients were collected from February 2021 to February 2023. Most had breast (n = 715, 35.2%), ovarian (n = 259, 12.7%), pancreatic (n = 85, 4.2%), or prostate cancer (n = 58, 2.9%). We observed 586 variants of uncertain significance (VUS) and 372 deleterious variants (DVs) across 487 patients, with 17.6% HRR-mutation positivity. HRR testing identified 120 (11.8%) BRCA1/2-positive, and 172 (16.9%) HRR-positive patients. With 51 DVs identified in 242 formalin-fixed paraffin-embedded (FFPE), testing for variant origin clarification was required in one case (0.4%). Most BRCA1/2 germline variants were DV (121 DVs, 26 VUS); in non-BRCA1/2 genes, VUS were ubiquitous (53 DVs, 132 VUS). In silico prediction identified additional 4.9% HRR and 1.2% BRCA1/2/ATM/CHEK2 mutation patients.

Our study represents one of the first reports about the incidence of DV and VUS in HRR genes, including genes beyond BRCA1/2, identified in cancer patients from Russia, assessed by NGS. In silico predictions of the observed HRR gene variants suggest that non-BRCA gene testing is likely to result in higher frequency of patients who are candidates for PARP inhibitor therapy. Continuing sequencing efforts should clarify interpretation of frequently observed non-BRCA VUS.

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.

Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting.

We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation.

Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE.

PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen.

CRD42023454079.

Combining poly ADP-ribose polymerase (PARP) and topoisomerase I inhibitors has demonstrated synergistic effects in in vivo models. This phase I trial evaluated rucaparib and irinotecan in metastatic solid tumors with homologous recombination deficiency.

This study enrolled patients in three cohorts to determine the tolerability and preliminary efficacy of (1) rucaparib 400 mg PO twice a day (days 1-7, 15-21) and irinotecan 65 mg/m2 intravenously once every 2 weeks; (2) rucaparib 400 mg PO twice a day (D1-7, 15-21) and irinotecan 100 mg/m2 once every 2 weeks; and (3) rucaparib 400 mg per os twice a day (D1-7) and irinotecan 100 mg/m2 once every 3 weeks.

Twenty patients were enrolled: 95% with previous platinum, 40% with previous irinotecan, and 20% with previous PARP inhibitor. The maximally tolerated was determined as rucaparib 400 mg twice a day days 1-7 and irinotecan 100 mg/m2 once every 3 weeks. Four dose-limiting toxicities (all grade 3-4 neutropenia) occurred during dose escalation with only neutropenia as other grade 3-4 toxicities (25%; grade 3 [n = 3], grade 4 [n = 2]). Treatment-related grade 1-2 adverse events included neutropenia (45%), diarrhea (45%), nausea (40%), and fatigue (30%). Of 17 patients with evaluable disease, six patients (35%) derived clinical benefit (n = 2 with PR, n = 4 with stable disease for over 6 months). Three patients remained on study >1 year: two with ATM mutations (small bowel carcinoma and pancreatic neuroendocrine tumor) and one patient with a PALB2 mutation (primary peritoneal cancer).

Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in BRCA-, PALB2-, and ATM-mutated cancers despite progression on previous platinum.

Genetic testing is an integral part of the workup of metastatic prostate cancer, in part, because the results can have a profound impact on the subsequent management of this disease. There are now several Food & Drug Administration (FDA) approved therapeutics available for patients with prostate cancer and certain genetic abnormalities - most notably, mutations in DNA damage repair (DDR) pathways such mismatch repair (MMR) and homologous recombination repair (HRR). In this review of the current literature, we discuss the indications for somatic and germline testing, the genetic changes of particular clinical relevance, the associated therapeutic options, and the clinical data supporting their use. We also highlight select trials-in-progress and future directions for the field.

Molecular profiling studies have shed new light on the complex biology of prostate cancer. Genomic studies have highlighted that structural rearrangements are among the most common recurrent alterations. In addition, both germline and somatic mutations in DNA repair genes are enriched in patients with advanced disease. Primary prostate cancer has long been known to be multifocal, but recent studies demonstrate that a large fraction of prostate cancer shows evidence of multiclonality, suggesting that genetically distinct, independently arising tumor clones coexist. Metastatic prostate cancer shows a high level of morphologic and molecular diversity, which is associated with resistance to systemic therapies. The resulting high level of intratumoral heterogeneity has important implications for diagnosis and poses major challenges for the implementation of molecular studies. Here we provide a concise review of the molecular pathology of prostate cancer, highlight clinically relevant alterations, and discuss opportunities for molecular testing.

Prostate cancer is a molecularly heterogeneous disease that is amenable to diagnostic testing to identify patients potentially eligible for personalised treatments inform familial risk and provide relevant information about potential prognosis. Several guidelines support the integration of genomic testing in a shared decision-making framework so that both health care professionals (HCPs) and patients are involved in determining the best treatment approach.

To review current guidelines on molecular diagnostic testing for homologous recombination repair (HRR) gene alterations in patients with metastatic prostate cancer, with the aim of providing practical considerations for effective guideline implementation and establishment of an appropriate pathway for molecular diagnostic testing.

We undertook a nonsystematic narrative review of the literature using PubMed to identify current guidelines and recommendations on molecular diagnostic testing for BRCA and/or homologous recombination repair gene alterations (HRRm) in patients with prostate cancer. In addition, selected articles that included BRCA/HRRm testing in clinical trials in metastatic castration-resistant prostate cancer and real-world evidence were also evaluated. Websites for relevant societies were reviewed for molecular diagnostic guidelines not published on PubMed.

Our review of guidelines published by several international societies that include molecular testing in prostate cancer identified variations in molecular testing approaches. The review of testing approaches used in clinical trials and real-world settings also highlighted several aspects that require improvement. Therefore, we compiled practical guidance for establishing an appropriate BRCA/HRR mutation testing pathway.

While there are several challenges to molecular testing and interpretation of test results that require enhancement, a multidisciplinary team approach will empower HCPs and their institutions to improve on or initiate their own molecular testing pathways. This in turn will lead to improvements in management strategies for patients with metastatic prostate cancer, for whom better treatment outcomes is a significant unmet need.

Establishing a molecular testing pathway in clinical practice for patients with metastatic castration-resistant prostate cancer will lead to fairer and more equal access to personalised treatments. This should lead to better outcomes, particularly for patients whose disease has spread to other areas of the body.

Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.

We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition.

ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition.

These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Over the last few decades, the incidence of urogenital cancers has exhibited diverse trends influenced by screening programs and geographical variations. Among women, there has been a consistent or even increased occurrence of endometrial and ovarian cancers; conversely, prostate cancer remains one of the most diagnosed malignancies, with a rise in reported cases, partly due to enhanced and improved screening efforts.Simultaneously, the landscape of cancer therapeutics has undergone a remarkable evolution, encompassing the introduction of targeted therapies and significant advancements in traditional chemotherapy. Modern targeted treatments aim to selectively address the molecular aberrations driving cancer, minimizing adverse effects on normal cells. However, traditional chemotherapy retains its crucial role, offering a broad-spectrum approach that, despite its wider range of side effects, remains indispensable in the treatment of various cancers, often working synergistically with targeted therapies to enhance overall efficacy.For urogenital cancers, especially ovarian and prostate cancers, DNA damage response inhibitors, such as PARP inhibitors, have emerged as promising therapeutic avenues. In BRCA-mutated ovarian cancer, PARP inhibitors like olaparib and niraparib have demonstrated efficacy, leading to their approval for specific indications. Similarly, patients with DNA damage response mutations have shown sensitivity to these agents in prostate cancer, heralding a new frontier in disease management. Furthermore, the progression of ovarian and prostate cancer is intricately linked to hormonal regulation. Ovarian cancer development has also been associated with prolonged exposure to estrogen, while testosterone and its metabolite dihydrotestosterone, can fuel the growth of prostate cancer cells. Thus, understanding the interplay between hormones, DNA damage and repair mechanisms can hold promise for exploring novel targeted therapies for ovarian and prostate tumors.In addition, it is of primary importance the use of preclinical models that mirror as close as possible the biological and genetic features of patients' tumors in order to effectively translate novel therapeutic findings "from the bench to the bedside".In summary, the complex landscape of urogenital cancers underscores the need for innovative approaches. Targeted therapy tailored to DNA repair mechanisms and hormone regulation might offer promising avenues for improving the management and outcomes for patients affected by ovarian and prostate cancers.

Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.

Prostatic acinar adenocarcinoma accounts for approximately 95% of prostate cancer (CaP) cases. The remaining 5% of histologic subtypes of CaP are known to be more aggressive and have recently garnered substantial attention. These histologic subtypes - namely, prostatic ductal adenocarcinoma (PDA), intraductal carcinoma of the prostate (IDC-P), and cribriform carcinoma of the prostate (CC-P) - typically exhibit distinct growth characteristics, genomic features, and unique oncologic outcomes. For example, PTEN mutations, which cause uncontrolled cell growth, are frequently present in IDC-P and CC-P. Germline mutations in homologous DNA recombination repair (HRR) genes (e.g., BRCA1, BRCA2, ATM, PALB2, and CHEK2) are discovered in 40% of patients with IDC-P, while only 9% of patients without ductal involvement had a germline mutation. CC-P is associated with deletions in common tumor suppressor genes, including PTEN, TP53, NKX3-1, MAP3K7, RB1, and CHD1. Evidence suggests abiraterone may be superior to docetaxel as a first-line treatment for patients with IDC-P. To address these and other critical pathological attributes, this review examines the molecular pathology, genetics, treatments, and oncologic outcomes associated with CC-P, PDA, and IDC-P with the objective of creating a comprehensive resource with a centralized repository of information on PDA, IDC-P, and CC-P.

Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as promising chemotherapeutic drugs primarily against BRCA1/2-associated tumours, known as synthetic lethality. However, recent clinical trials reported patients' survival benefits from PARP inhibitor treatments, irrelevant to homologous recombination deficiency. Therefore, revealing the therapeutic mechanism of PARP inhibitors beyond DNA damage repair is urgently needed, which can facilitate precision medicine.

A CRISPR-based knock-in technology was used to establish stable BRCA1 mutant cancer cells. The effects of PARP inhibitors on BRCA1 mutant cancer cells were evaluated by biochemical and cell biological experiments. Finally, we validated its in vivo effects in xenograft and patient-derived xenograft (PDX) tumour mice.

In this study, we uncovered that the majority of clinical BRCA1 mutations in breast cancers were in and near the middle of the gene, rather than in essential regions for DNA damage repair. Representative mutations such as R1085I and E1222Q caused transient extra spindle poles during mitosis in cancer cells. PAR, which is synthesized by PARP2 but not PARP1 at mitotic centrosomes, clustered these transient extra poles, independent of DNA damage response. Common PARP inhibitors could effectively suppress PARP2-synthesized PAR and induce cell senescence by abrogating the correction of mitotic extra-pole error.

Our findings uncover an alternative mechanism by which PARP inhibitors efficiently suppress tumours, thereby pointing to a potential new therapeutic strategy for centrosome error-related tumours.

Funded by National Natural Science Foundation of China (NSFC) (T2225006, 82272948, 82103106), Beijing Municipal Natural Science Foundation (Key program Z220011), and the National Clinical Key Specialty Construction Program, P. R. China (2023).

The treatment of metastatic castration-resistant prostate cancer (mCRPC) has been fundamentally transformed by our greater understanding of its complex biological mechanisms and its entrance into the era of precision oncology. A broad aim is to use the extreme heterogeneity of mCRPC by matching already approved or new targeted therapies to the correct tumor genotype. To achieve this, tumor DNA must be obtained, sequenced, and correctly interpreted, with individual aberrations explored for their druggability, taking into account the hierarchy of driving molecular pathways. Although tumor tissue sequencing is the gold standard, tumor tissue can be challenging to obtain, and a biopsy from one metastatic site or primary tumor may not provide an accurate representation of the current genetic underpinning. Sequencing of circulating tumor DNA (ctDNA) might catalyze precision oncology in mCRPC, as it enables real-time observation of genomic changes in tumors and allows for monitoring of treatment response and identification of resistance mechanisms. Moreover, ctDNA can be used to identify mutations that may not be detected in solitary metastatic lesions and can provide a more in-depth understanding of inter- and intra-tumor heterogeneity. Finally, ctDNA abundance can serve as a prognostic biomarker in patients with mCRPC.The androgen receptor (AR)-axis is a well-established therapeutical target for prostate cancer, and through ctDNA sequencing, insights have been obtained in (temporal) resistance mechanisms that develop through castration resistance. New third-generation AR-axis inhibitors are being developed to overcome some of these resistance mechanisms. The druggability of defects in the DNA damage repair machinery has impacted the treatment landscape of mCRPC in recent years. For patients with deleterious gene aberrations in genes linked to homologous recombination, particularly BRCA1 or BRCA2, PARP inhibitors have shown efficacy compared to the standard of care armamentarium, but platinum-based chemotherapy may be equally effective. A hierarchy exists in genes associated with homologous recombination, where, besides the canonical genes in this pathway, not every other gene aberration predicts the same likelihood of response. Moreover, evidence is emerging on cross-resistance between therapies such as PARP inhibitors, platinum-based chemotherapy and even radioligand therapy that target this genotype. Mismatch repair-deficient patients can experience a beneficial response to immune checkpoint inhibitors. Activation of other cellular signaling pathways such as PI3K, cell cycle, and MAPK have shown limited success with monotherapy, but there is potential in co-targeting these pathways with combination therapy, either already witnessed or anticipated. This review outlines precision medicine in mCRPC, zooming in on the role of ctDNA, to identify genomic biomarkers that may be used to tailor molecularly targeted therapies. The most common druggable pathways and outcomes of therapies matched to these pathways are discussed.

There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test.

The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB.

Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients.

Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.