PARP Inhibitors Research Articles

Case report: Long-term progression-free survival in advanced ovarian cancer treated with apatinib in first-line maintenance treatment

Ovarian cancer is one of the most common gynecological malignancies. The current first-line treatment strategies for advanced ovarian cancer include surgery, chemotherapy, and maintenance therapy. Bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi) are primary maintenance treatments for advanced ovarian cancer. Previously, many patients declined these therapies before medicare coverage because of high costs. Bevacizumab and apatinib are anti-tumor angiogenic agents. In this case study, we describe a patient with advanced ovarian cancer who underwent neoadjuvant chemotherapy, interval debulking surgery, and adjuvant chemotherapy. She declined bevacizumab and PARPi maintenance therapy owing to the prohibitive expenses. The patient was administered off-label apatinib and achieved a progression-free survival of 54 months. Thus, apatinib may offer substantial therapeutic value as a first-line maintenance therapy in advanced ovarian cancer.

Celastrol attenuates the invasion and migration and augments the anticancer effects of olaparib in prostate cancer

BackgroundProstate cancer (PCa) is a leading malignancy among men globally, with rising incidence rates emphasizing the critical need for better detection and therapeutic approaches. The roles of HSP90AB1 and PARP1 in prostate cancer cells suggest potential targets for enhancing treatment efficacy.MethodsThis study investigated the overexpression of HSP90AB1 and PARP1 in prostate cancer cells and the impact of HSP90AB1 knockdown on the sensitivity of these cells to the PARP inhibitor olaparib. We also explored the combined effect of olaparib and celastrol, an HSP90 inhibitor, on the clonogenic survival, migration, proliferation, and overall viability of prostate cancer cells, alongside the modulation of the PI3K/AKT pathway. An in vivo PC3 xenograft mouse model was used to assess the antitumor effects of the combined treatment.ResultsOur findings revealed significant overexpression of HSP90AB1 and PARP1 in prostate cancer cells. Knockdown of HSP90AB1 increased cell sensitivity to olaparib. The combination of olaparib and celastrol significantly reduced prostate cancer cell survival, migration, proliferation, and enhanced cumulative DNA damage. Celastrol also downregulated the PI3K/AKT pathway, increasing cell susceptibility to olaparib. In vivo experiments demonstrated that celastrol and olaparib together exerted strong antitumor effects.ConclusionsThe study indicates that targeting both HSP90AB1 and PARP1 presents a promising therapeutic strategy for prostate cancer. The synergistic combination of celastrol and olaparib enhances the efficacy of treatment against prostate cancer, offering a potent approach to combat this disease.

Usefulness of Nutritional Assessment Indicators in Predicting Treatment Discontinuation Due to Adverse Events from PARP Inhibitors in Ovarian Cancer Patients

Background: Nutritional status is an important factor influencing toxicity of treatment. Nutritional assessment indicators such as the Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT) score and modified Glasgow Prognostic Score (mGPS) have been reported to be associated with treatment-related adverse events (AEs) for various malignancies. However, there are no reports investigating the relationship between nutritional status and AEs from poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which are widely used in recent years as maintenance therapy for ovarian cancer. Objective: The primary objective was to investigate the usefulness of nutritional assessment indicators in predicting treatment discontinuation due to AEs from PARPi. Methods: This multicenter retrospective study included patients diagnosed with ovarian cancer who received maintenance therapy with PARPi from January 2018 to December 2023. PNI, CONUT score, and mGPS were calculated based on hematological parameters measured within 7 days before the start of PARPi therapy. Results: A total of 272 patients received maintenance therapy with PARPi during the period, but due to the absence of the blood collection of albumin levels within one week or other exclusion criteria, 71 patients were finally included in this analysis. AEs were seen in 59 patients (83.1%), including 25 (35.2%) severe events (grade ≥3 in Common Terminology Criteria for Adverse Events v5.0). Eighteen patients (25.4%) discontinued treatment due to PARPi-related AEs. Low PNI (<48.44) and high mGPS (≥1) were predictors of treatment discontinuation in both univariate and multivariate analyses. CONUT was not a significant predictor in this study. Conclusions: Our study suggested that PNI and mGPS can predict the risk of treatment discontinuation due to PARPi-related AEs before starting maintenance therapy. This insight opens avenues for more personalized treatment plans, potentially improving patient outcomes.

Germline DNA damage repair variants and prognosis of patients with high-risk or metastatic prostate cancer.

Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk, localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Among 3,525 patients initially diagnosed with non-metastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 mCSPC, and 502 mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.69, 1.46) or overall survival in mCSPC (HR 0.46, 95% CI 0.14, 1.45) or mCRPC (HR 0.60, 95% CI 0.31, 1.17) compared to non-carriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR 1.59, 95% CI 1.01, 2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for non-metastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis.

Prostate Cancer, Pathophysiology and Recent Developments in Management: A Narrative Review.

Prostate cancer is the second most common cancer in men. The different stages of prostate cancer which include localised (low, intermediate, and high risk) disease, locally advanced, non-metastatic castration-resistant prostate cancer (M0 CRPCa), and metastatic disease. The main treatment of locally advanced disease is external beam radiotherapy with hormonal therapy which are associated with good prognosis. Current treatments for M0 CRPCa include androgen deprivation therapy in combination with apalutamide, darolutamide or enzalutamide, all of which are associated with good metastatic-free survival rates in clinical trials. Hormone-naive metastatic prostate cancer comprises the same treatments as M0 CRPCa, whereas further treatment includes docetaxel and abiraterone. Metastatic castration-resistant prostate cancer treatments include sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, which aim to slow down the progression of the disease and to prolong life. This article also provides insight into the development of new drugs recently approved for metastatic castration prostate cancer, which include PARP inhibitors and Lutetium-177 which have shown to have significantly good overall survival and to improve radiographic progression-free survival. In addition, new clinical trials are ongoing to test new medications such as cabozantinb and chimeric-antigen receptor T-cell therapy for the treatment of advanced prostate cancer. With the aim to slow down the progression of the disease and to prolong life, new drug developments are underway to hopefully provide a positive impact on overall survival and improve progression-free survival, especially in advanced prostate cancer.

Consensus on drivers of maintenance treatment choice and patterns of care in advanced ovarian cancer

ObjectivesMaintenance therapies, including poly (ADP-ribose) polymerase (PARP) inhibitors and/or bevacizumab, have substantially improved the prognosis of patients with advanced ovarian cancer. Owing to the variability in treatment strategies across Europe,...

PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells.

Olaparib, a PARP inhibitor, is a targeted therapy used in treating various cancers including castration-resistant prostate cancer (CRPC). Despite its efficacy, resistance to Olaparib remains a significant challenge. Understanding the molecular mechanisms underpinning this resistance is crucial for developing more effective treatment strategies. This study focuses on elucidating the role of mitochondrial alterations and the PINK1 gene in conferring Olaparib resistance in CRPC cells. We investigated the transcriptomic and functional differences in mitochondrial activity between Olaparib-resistant (2B-OlapR, LN-OlapR) and treatment naïve prostate cancer (PCa) cells (C4-2B, LNCaP) in both castration sentitive and resistant settings. Through RNA sequencing and Gene Set Enrichment Analysis (GSEA), we identified significant enrichment of mitochondrial and oxidative phosphorylation-related gene sets in Olaparib Resistant derived cell lines. Resistant lines exhibited enhanced mitochondrial functionality including increased basal and maximal respiration rates, as well as elevated ATP production and spare respiratory capacity compared to parental cells. Subsequent investigations revealed a substantial increase in mitochondrial mass and electron transport chain complex I activity in Olaparib-resistant cells. Furthermore, overexpression of the PINK1 gene was observed in resistant cells, which was correlated with resistance to Olaparib and poor clinical outcomes in prostate cancer patients. Inhibition of PINK1 expression significantly reduced mitochondrial function and mass, impaired cell growth, and decreased resistance to Olaparib. These findings suggest that PINK1 plays a crucial role in modulating mitochondrial dynamics that confer therapeutic resistance, highlighting its potential as a therapeutic target for overcoming Olaparib resistance in PCa.

Olaparib: A Chemosensitizer for the Treatment of Glioblastoma.

Glioblastoma (GBM) is the most prevalent and deadly primary brain tumor. The current treatment for GBM includes adjuvant chemotherapy with temozolomide (TMZ), radiation therapy, and surgical tumor excision. There is still an issue because 50% of patients with GBM who get TMZ have low survival rates due to TMZ resistance. The activation of several DNA repair mechanisms, such as Base Excision Repair (BER), DNA Mismatch Repair (MMR), and O-6- Methylguanine-DNA Methyltransferase (MGMT), is the main mechanism via which TMZ resistance develops. The zinc-finger DNA-binding enzyme poly (ADP-ribose) polymerase-1 (PARP1), which is activated by binding to DNA breaks, affects the activation of the MGMT, BER, and MMR pathway deficiency, which results in TMZ resistance in GBM. PARP inhibitors have been studied recently as sensitizing medications to increase TMZ potency. The first member of the PARP inhibitor family to be identified was Olaparib. It inhibits PARP1 and PARP2, which causes apoptosis in cancer cells and DNA strand break. Olaparib is currently investigated as a radio- and/or chemo-sensitizer in addition to being used as a single agent because it may increase the cytotoxic effects of other treatments. This review addresses Olaparib and its significance in treating TMZ resistance in GBM.

How long is long enough? An international survey exploring practice variations on the recommended duration of maintenance therapy with PARP inhibitors in patients with platinum sensitive recurrent ovarian cancer and long-term outcomes

ObjectiveThere are no data, and thus no consensus, on the optimal duration of poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy for exceptional responders (here defined as progression-free for 5 years or...

Emergence of cyclic hypoxia and the impact of PARP inhibitors on tumor progression.

Tumor hypoxia is a dynamic phenomenon marked by fluctuations in oxygen levels across both rapid (seconds to minutes) and slow (hours to days) time scales. While short hypoxia cycles are relatively well understood, the mechanisms behind longer cycles remain largely unclear. In this paper, we present a novel mechanistic mathematical model that explains slow hypoxia cycles through feedback loops involving vascular expansion and regression, oxygen-regulated tumor growth, and toxic cytokine production. Our study reveals that, for the emergence of slow hypoxia cycles, endothelial cells must adapt by decreasing receptor activation as ligand concentration increases. Additionally, the interaction between tumor cells and toxic cytokines influences frequency and intensity of these cycles. By examining the effects of pharmacological interventions, specifically poly (ADP-ribose) polymerase inhibitors, we also demonstrate how targeting cell proliferation can help regulate oxygen levels. Our findings enhance the understanding of hypoxia regulation and suggest PARP proteins as promising therapeutic targets.

Poly (ADP-Ribose) Polymerase 1 Induces Cyclic GMP-AMP Synthase-stimulator of Interferon Genes Pathway Dysregulation to Promote Immune Escape of Colorectal Cancer Cells

Colorectal cancer (CRC) ranks third globally in cancer incidence and mortality, posing a significant human concern. Recent advancements in immunotherapy are noteworthy. This study explores immune modulation for CRC treatment. Initially targeting poly (ADP-ribose) polymerase 1 (PARP-1), a gene overexpressed in CRC tissues per The Cancer Genome Atlas, we examined its correlation with immune cell infiltration using the Tumor Immune Estimation Resource tool. Quantitative reverse transcription polymerase chain reaction assessed PARP-1 mRNA and inflammation-related gene expression in tumor tissues and cells. Assessing CD8+ T-cell proliferation and cytotoxicity towards HCT116 cells involved carboxyfluorescein diacetate succinimidyl ester and lactate dehydrogenase kits. Chemotaxis was gauged using a Transwell system in a CD8+ T-cell coculture setup, with immunofluorescence revealing cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) levels in HCT116 cells. Enzyme-linked immunosorbent assay kits measured CD8+ T-cell cytokine secretion. The findings suggested that PARP-1 was overexpressed in CRC tissues and cells and this overexpression was positively correlated with Treg cell infiltration. Overexpression of PARP-1 could significantly reduce the proportion of cGAS and STING-positive cells in HCT116 cells, dampen the proliferation, tumor-killing capacity, and chemotaxis of CD8+ T cells, and inhibit the secretion of related cytokines. The introduction of STING agonists could reverse the effects caused by overexpressed PARP-1. In vivo experiments affirmed the independent anti-tumor effects of PARP-1 inhibitors and STING agonists, synergistically inhibiting tumor growth. Silencing PARP-1 in HCT116 cells potentially boosts CD8+ T-cell activity against these cells through the cGAS-STING pathway.

Impact of PARP inhibitors on progression-free survival in platinum-sensitive recurrent epithelial ovarian cancer: a retrospective analysis

ObjectivePoly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib and niraparib have shown promise in extending progression-free survival (PFS) in patients with platinum-sensitive recurrent (PSR) epithelial ovarian cancer. In this retrospective study, we aimed to present our own data on the effect of PARP inhibitors on PFS in recurrent epithelial ovarian cancer.Methods82 patients diagnosed with PSR epithelial ovarian, tubal, or primary peritoneal cancer between May 2017 and September 2023 were initially enrolled from our hospital. However, 16 patients had prior exposure to PARP inhibitors during primary treatment, and 11 were lost to follow-up. Consequently, the study focused on 55 eligible patients. PFS was compared between patients receiving PARP inhibitor maintenance therapy and those who did not.ResultsAmong the 55 patients with PSR epithelial ovarian cancer, 18 received olaparib as maintenance therapy, 19 received niraparib, and 18 opted for observation. PARP inhibitor therapy significantly extended PFS (mean 24.0 months) compared to observation (mean 9.0 months, p = 0.0005), regardless of BRCA mutation status (HR = 0.20, 95% CI: 0.08–0.50). Subgroup analysis showed no statistical difference between olaparib and niraparib. Additionally, there was no PFS difference based on BRCA mutation status within both PARP inhibitor groups.ConclusionOur retrospective study demonstrates that PARP inhibitor maintenance therapy, including olaparib and niraparib, significantly prolongs PFS in patients with PSR epithelial ovarian, tubal, or primary peritoneal cancer, These findings support the broad utilization of PARP inhibitors as a standard maintenance therapy for PSR epithelial ovarian cancer irrespective of BRCA mutation status.

Identification of three subtypes of ovarian cancer and construction of prognostic models based on immune-related genes

BackgroundImmunotherapy has revolutionized the treatment of ovarian cancer (OC), but different immune microenvironments often constrain the efficacy of immunotherapeutic interventions. Therefore, there is an imperative to delineate novel immune subtypes for development of efficacious immunotherapeutic strategies.MethodsThe immune subtypes of OC were identified by consensus cluster analysis. The differences in clinical features, genetic mutations, mRNA stemness (mRNAsi) and immune microenvironments were analyzed among subtypes. Subsequently, prognostic risk models were constructed based on differentially expressed genes (DEGs) of the immune subtypes using weighted correlation network analysis.ResultsOC patients were classified into three immune subtypes with distinct survival rates and clinical features. Different subtypes exhibited varying tumor mutation burdens, homologous recombination deficiencies, and mRNAsi levels. Significant differences were observed among immune subtypes in terms of immune checkpoint expression and immunogenic cell death. Prognostic risk models were validated as independent prognostic factors demonstrated great predictive performance for survival of OC patients.ConclusionIn this study, three distinct immune subtypes were identified based on gene sets related to vaccine response, with the C2 subtype exhibiting significantly worse prognosis. While no statistically significant differences in tumor mutation burden (TMB) were observed across the three subtypes, the homologous recombination deficiency (HRD) score and mRNA stemness index (mRNAsi) were notably elevated in the C2 group compared to the others. Immune infiltration analysis indicated that the C2 subtype may have an increased presence of regulatory T (Treg) cells, potentially contributing to a more favorable response to combination therapies involving PARP inhibitors and immunotherapy. These findings offer a precision medicine approach for tailoring immunotherapy in ovarian cancer patients. Moreover, the C3 subtype demonstrated significantly lower expression levels of immune checkpoint genes, a pattern validated by independent datasets, and associated with a better prognosis. Further investigation revealed that the immune-related gene FCRL5 correlates with ovarian cancer prognosis, with in vitro experiments showing that it influences the proliferation and migration of the ovarian cancer cell line SKOV3.

The efficacy of Veliparib in combination with chemotherapy in the treatment of lung cancer: systematic review and meta-analysis.

This meta-analysis aims to examine the effectiveness of veliparib, a poly ADP-ribose polymerase inhibitor, in combination with chemotherapy in treating bronchogenic carcinoma. PubMed, Cochrane, Scopus, and Web of Science were searched for eligible randomized controlled trials comparing veliparib plus chemotherapy to standard chemotherapy in adult lung cancer patients, until July 2023. The main outcomes were overall survival (OS) and progression-free survival (PFS). This meta-analysis included six studies encompassing 2,136 patients. Veliparib has a slight OS improvement over placebo, HR = 0.91, 95% CI [0.83 to 1.0], p = 0.05. Veliparib offers more OS benefit in the subpopulation of non-small cell lung cancer (NSCLC) than small-cell lung cancer (SCLC), HR = 0.89, 95% CI [0.81,0.99], p = 0.03 and HR = 1.00, 95% CI [0.79, 1.28], p = 0.97, respectively. There was no significant PFS benefit between the two groups, HR = 0.92, 95% CI [0.81-1.01], p = 0.08). Veliparib has a marginal inclination for overall survival improvement, more so in NSCLC, with an acceptable safety profile. Our results merit the pursuit of better-powered trials to support further the extent of veliparib's effectiveness in lung cancer patients. PROSPERO (CRD42023453705).

Positioning loss of PARP1 activity as the central toxic event in BRCA-deficient cancer

The mechanisms by which poly(ADP-ribose) polymerase 1 (PARP1) inhibitors (PARPi)s inflict replication stress and/or DNA damage are potentially numerous. PARPi toxicity could derive from loss of its catalytic activity and/or its physical trapping of PARP1 onto DNA that perturbs not only PARP1 function in DNA repair and DNA replication, but also obstructs compensating pathways. The combined disruption of PARP1 with either of the hereditary breast and ovarian cancer genes, BRCA1 or BRCA2 (BRCA), results in synthetic lethality. This has driven the development of PARP inhibitors as therapies for BRCA-mutant cancers. In this review, we focus on recent findings that highlight loss of PARP1 catalytic activity, rather than PARPi-induced allosteric trapping, as central to PARPi efficacy in BRCA deficient cells. However, we also review findings that PARP-trapping is an effective strategy in other genetic deficiencies. Together, we conclude that the mechanism-of-action of PARP inhibitors is not unilateral; with loss of activity or enhanced trapping differentially killing depending on the genetic context. Therefore, effectively targeting cancer cells requires an intricate understanding of their key underlying vulnerabilities.

The Role of Tumor Biomarkers in Tailoring the Approach to Advanced Ovarian Cancer

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD’s connection with platinum-based therapy and PARP inhibitors’ response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool.

Nanotechnology strategy for inhibition of PARP1 and IL-17A-associated with neurotoxicity in rats exposed to hospital wastewater.

Hospital wastewater (HWW) poses a serious hazard to human health security concerning its high susceptibility to neurodegeneration. Water sources and ecosystems are exposed to a complicated pollution load from a variety of refractory organics and pharmaceutical active composites. This study evaluates the treated newly developed nanocomposite (NiFe2O4) HWW on the neural injury induced by HWW action in rats. Three groups of male Wistar rats were distributed, with eight rats in each: group I: tap water served as a control; group II: HWW; and group III: nano-HWW. Each group was intragastrical administrated with each type of water (2.5 ml/100 g b.wt/6 h) for 28 consecutive days. The open field test and Morris Water Maze assessed behavioral activity and spatial learning 2 days before the last day. The research demonstrated that HWW treated with nanocomposite (NiFe2O4) may exert decreased risks of the neural impairment effect of HWW. This improvement was achieved by reducing the neurotoxicity by lowering nitric oxide contents, lipid peroxidation, acetylcholinesterase, interleukin-17A (IL-17A), and poly(ADP-ribose) polymerase1(PARP1) while restoring the antioxidant biomarkers and neurotransmitter levels (β-endorphin, norepinephrine, dopamine, and serotonin) of the treated groups in the cortex and brainstem and enhancement of the histopathology of the cortex as well. In conclusion, this study introduced a newly developed nanotechnology application for treating HWW to protect from neural injury. The findings of this research have significant value for policymakers, Ministry of Health management, and environmental organizations in their selection of suitable techniques and procedures to optimize hospital wastewater treatment efficiency.

Exploring and comparing renal adverse effects between PARP inhibitors based on a real-world analysis of post-marketing surveillance data

Exploring and comparing renal adverse effects between PARP inhibitors based on a real-world analysis of post-marketing surveillance data

PARP Pioneers: Using BRCA1/2 Mutation-targeted Inhibition to Revolutionize Breast Cancer Treatment.

Breast Cancer stands on the second position in the world in being common and women happen to have it with high rate of about five-folds around the world. The causes of occurrence can matter with different humans be it external factors or the internal genetic ones. Breast cancer is primarily driven by mutations in the BRCA1 and BRCA2 susceptibility genes. These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). Poly (ADP ribose) polymerases (PARP) are the essential enzymes involved in the repairing of the damaged DNA. So the inhibition of these inhibitors can be considered as the promising strategy for targeting cancers with defective damage in the deoxyribonucleic acid. Olaparib and talazoparib are PARP inhibitors (PARPi) are being employed for the monotherapies in case of the deleterious germline HER2-negative and BRCA-mutated breast cancer. The potency of PARP for trapping on DNA and causes cytotoxicity may have difference in the safety and efficacy with the PARPi. The PARPi have been found its place in the all different types of Breast Cancers and have shown potential benefits. The purpose of this review is to provide an update on the oral poly(ADP-ribose) polymerase (PARP)inhibitors for the improvement in the treatment and management of Breast Cancer.

Navigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey.

Novel therapies for metastatic castration-resistant prostate cancer (mCRPC) have improved patient outcomes. However, there is uncertainty on the optimal selection of therapeutic agents for subsequent lines of therapy. We conducted a comprehensive review of published evidence from pivotal clinical trials and recent guidelines for the treatment of mCRPC. We further identify gaps in knowledge and areas for future research. Key considerations to help guide treatment selection for patients with mCRPC include personal treatment history, individual clinical characteristics, symptoms, prognosis, availability of clinical trials, and other patient-specific factors. Genetic testing and prostate-specific membrane antigen-targeted imaging are important tools to evaluate candidacy for newer therapeutic options such as poly (ADP-ribose) polymerase inhibitors, alone or in combination with androgen receptor pathway inhibitors, and [177Lu]Lu-PSMA-617. This article provides an overview of the evolving treatment landscape of mCRPC, discussing guideline-recommended treatment options and data from key clinical trials, while highlighting ongoing trials that may impact the future treatment landscape. Recommendations for optimal treatment sequencing based on individual patient factors are provided.