Key Clinical Trials Research Articles

Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive genetic condition that is caused by variants in the cystic fibrosis transmembrane conductance regulator gene. This causes multisystem disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel at the apical surface of epithelia. Until recently, treatment was directed at managing the downstream effects in affected organs, principally improving airway clearance and treating infection in the lungs and improving malabsorption in the gastrointestinal tract. Care delivered by multidisciplinary teams has yielded incremental improvements in outcomes. However, the development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics. Modulators target the underlying defect and improve CFTR function. Either monotherapy or a combination of modulators is used depending on the specific genotype and class of CFTR disease-causing variants that an individual has. Both ivacaftor and the ivacaftor/tezacaftor/elexacaftor combination have been demonstrated to be associated with clinically very significant benefits in randomised trials and have rapidly been made available as part of standard care in many countries. CFTR modulators represent one of the best examples of precision medicine to date. They are expensive, however, and equity of access to them worldwide remains an issue. Studies and approvals are also ongoing for children under the age of 6 years for ivacaftor/tezacaftor/elexacaftor. Furthermore, no modulators are available for around 10% of the people with CF. In this review, we firstly summarise the genetics, pathophysiology and clinical problems associated with CF. We then discuss the development of CFTR modulators and key clinical trials to support their use along with other potential future therapeutic approaches.

Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives.

The paradigm of antivirulence therapy dictates that bacterial pathogens are specifically disarmed but not killed by neutralizing their virulence factors. Clearance of the invading pathogen by the immune system is promoted. As compared to antibiotics, the pathogen-selective antivirulence drugs hold promise to minimize collateral damage to the beneficial microbiome. Also, selective pressure for resistance is expected to be lower because bacterial viability is not directly affected. Antivirulence drugs are being developed for stand-alone prophylactic and therapeutic treatments but also for combinatorial use with antibiotics. This Review focuses on drug modalities that target bacterial exotoxins after the secretion or release-upon-lysis. Exotoxins have a significant and sometimes the primary role as the disease-causing virulence factor, and thereby they are attractive targets for drug development. We describe the key pre-clinical and clinical trial data that have led to the approval of currently used exotoxin-targeted drugs, namely the monoclonal antibodies bezlotoxumab (toxin B/TcdB, Clostridioides difficile), raxibacumab (anthrax toxin, Bacillus anthracis), and obiltoxaximab (anthrax toxin, Bacillus anthracis), but also to challenges with some of the promising leads. We also highlight the recent developments in pre-clinical research sector to develop exotoxin-targeted drug modalities, i.e., monoclonal antibodies, antibody fragments, antibody mimetics, receptor analogs, neutralizing scaffolds, dominant-negative mutants, and small molecules. We describe how these exotoxin-targeted drug modalities work with high-resolution structural knowledge and highlight their advantages and disadvantages as antibiotic alternatives.

Targeting HER2+ Breast Cancer Brain Metastases: A Review of Brain-Directed HER2-Directed Therapies.

Despite advances in the treatment of metastatic, HER2+ breast cancer, the development of central nervous system metastases remains a therapeutic challenge. The challenge is amplified by the exclusion of patients with active brain metastases from many clinical trials. Initial HER2-targeted therapies, such as trastuzumab and pertuzumab, have shown limited efficacy for patients with brain metastases. In addition, the landscape of systemic therapy for HER2+ metastatic breast cancer is changing rapidly. In recent years, the development of small-molecule inhibitors in combination with chemotherapy has shown promise, though the efficacy is often balanced by key toxicities. Other HER2-targeted therapies, including antibody-drug conjugates, have presented new therapeutic options for this patient population; however, additional data for both small-molecule inhibitors and antibody-drug conjugates with respect to patients with central nervous system metastases is needed. Here, we specifically review the data for the management of HER2+ parenchymal brain metastases. A limited discussion of leptomeningeal disease is included; a more detailed review of this specific subgroup is outside the scope of this article. Key clinical trial data supporting the use of HER2-targeted and non-targeted therapies, including monoclonal antibodies and antibody-drug conjugates, are reviewed, with a specific focus on the use of HER2-targeted small-molecule inhibitors. We also review future directions and provide an overview of ongoing clinical trials which include patients with HER2+ brain metastases. With future focus on inclusive clinical trial design, particularly inclusion of patients with brain metastases, optimal strategies for management will be better elucidated.

High-intermediate risk endometrial cancer: moving toward a molecularly based risk assessment profile.

In the USA, endometrial cancer (EMCA) incidence is increasing as the risk factors of obesity, diabetes, and hypertension become more prevalent. Although most EMCA is detected at an early stage and surgical intervention is curative, a subset of patients termed 'high-intermediate risk' (H-IR) experience an increased rate of recurrence. Unfortunately, adjuvant therapies in patients with H-IR EMCA have yet to increase overall survival. Historically, stratification of these patients from their low-risk counterparts incorporated clinical and pathologic findings. However, due to developments in molecular testing and genomic sequencing, tumor biomarkers are now being incorporated into the risk-assessment criteria in the hope of finding molecular profile(s) that could highlight treatment regimens that will increase patient survival. Since modern research aims to accurately identify patients with a higher risk of recurrence and develop effective interventions to improve patient survival, these molecular-based analyses could allow for an enhanced understanding of a patient's true risk of recurrence to facilitate the rise of personalized medicine. This review summarizes key clinical trials and recent advances in molecular and genomic profiles that have influenced current treatment regimens for patients with H-IR EMCA and laid the foundation for subsequent research.

Treatment of macular diseases: an overview of key randomized clinical trials

Macular diseases are traditionally a serious issue in ophthalmology, which has great social impact due to widespread occurrence and significant vision loss, often irreversible. Over the past few decades, the possibilities for the diagnosis and treatment of pathologies of the retina and choroid have been significantly expanded. Randomized clinical trials provided ophthalmologists with valuable information on the natural course and treatment strategies of common retinal diseases from the viewpoint of evidence-based medicine. However, due to the large number of trials conducted, it is often difficult to make an adequate choice of data to be used in daily practice. In this review, we systematize the most valuable randomized clinical trials. To this end, we selected 42 randomized clinical studies conducted between 1979 and 2019 and focused on the treatment of age-related macular degeneration (AREDS 1, AREDS 2, ANCHOR, MARINA, PrONTO, CATT, IVAN, VIEW 1, VIEW 2, EVEREST II, PLANET, SEVEN-UP, ALTAIR, HAWK, HARRIER), choroidal neovascularization of multiple etiology (myopic, post-inflammatory, angioid-streak-related, etc. — RADIANCE, REPAIR, MYRROR, MINERVA), diabetic eye lesions (diabetic retinopathy and diabetic macular edema — ETDRS, DRCR.net Protocols B, I, S and T, RISE, RIDE, VIVID-DME, VISTA-DME, MEAD, FAME), retinal vein occlusions (BVOS, CVOS, SCORE-CRVO, SCORE-BRVO, BRAVO, CRUISE, GALILEO, COPERNICUS, VIBRANT), as well as retinopathy of prematurity (CRYO-ROP, ETROP, RAINBOW). The review summarizes the main results of these studies, which confirm the effectiveness and safety of such treatment methods as antiVEGF and photodynamic therapy, retinal laser photocoagulation, cryotherapy, corticosteroids and nutraceuticals from the viewpoint of evidence-based medicine. For greater clarity, we provide a table summarizing information on each of the randomized clinical trials considered.

Estimated Aggregate Treatment Benefit With Addition of Multiple Novel Medications for Secondary Prevention of Atherosclerotic Cardiovascular Disease.

Interest in improving residual cardiovascular (CV) risk by targeting multiple causative pathways has been growing. Several medications including icosapent ethyl, rivaroxaban, and ezetimibe have been shown to individually improve outcomes in the secondary prevention of atherosclerotic cardiovascular disease (ASCVD) beyond conventional therapy consisting of aspirin and statins. While each drug has been shown to individually improve outcomes, the expected treatment benefit of the combined use of these drugs for enhanced secondary prevention of ASCVD is not known. In this cross-trial analysis, we estimated the aggregate treatment effect of comprehensive medical therapy consisting of icosapent ethyl, rivaroxaban, and ezetimibe added to background aspirin and statin therapy through established methods of indirect comparisons of the results of three key clinical trials (REDUCE-IT [n = 8,179], COMPASS [n = 27,395], and IMPROVE-IT [n = 18,144]). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary endpoints included each individual component of the primary endpoint. The hazard ratio (HR) of the imputed aggregate treatment effects for enhanced secondary prevention of ASCVD with comprehensive disease modifying therapy compared to aspirin and statin alone for the primary endpoint was 0.51 (95% confidence interval [CI] 0.42-0.61). The HR for CV death was 0.62 (95% CI 0.46-0.85), non-fatal MI was 0.52 (95% CI 0.40-0.69), and non-fatal stroke was 0.35 (95% CI 0.23-0.54). The results were similar in sensitivity analyses. The estimated aggregate treatment effect of enhanced secondary prevention of ASCVD through comprehensive medical therapy is substantial. This exploratory analysis supports further study of comprehensive therapy to reduce residual CV risk for the secondary prevention of ASCVD.

Zanubrutinib for the Treatment of B-cell Malignancies

Selective Bruton's tyrosine kinase (BTK) inhibition is an important therapeutic approach for B-cell malignancies. Ibrutinib, a first-in-class, oral, irreversible BTK inhibitor, has a toxicity profile attributed to off-target inhibition of kinases structurally related to BTK. A highly potent and selective next-generation BTK inhibitor, zanubrutinib, was designed to address intolerance and toxicity concerns associated with ibrutinib. Zanubrutinib provides complete and sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes, with reduced toxicity compared with ibrutinib. Zanubrutinib received accelerated approval in the USA for patients with previously treated mantle cell lymphoma (2019) and relapsed/refractory (R/R) marginal zone lymphoma (2021) and was approved for Waldenström's macroglobulinaemia (WM) in 2021. Key clinical trials evaluating the efficacy and safety of zanubrutinib include the ASPEN study in patients with WM (ClinicalTrials.gov identifier: NCT03053440), the ALPINE study in patients with R/R chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL; ClinicalTrials.gov identifier: NCT03734016) and the SEQUOIA study in treatment-naïve patients with CLL/SLL with and without del(17p) mutation (ClinicalTrials.gov identifier: NCT03336333). The more selective BTK binding profile, high potency, favourable pharmacokinetic and pharmacodynamic profile, and minimal cardiovascular toxicity of zanubrutinib compared with ibrutinib suggest that zanubrutinib may be an important treatment option when prescribed in accordance with guidelines.

Current Advances in Immunotherapy for Glioblastoma Multiforme and Future Prospects.

Glioblastoma is the most frequent and malignant type of brain tumor. It has a reputation for being resistant to current treatments, and the prognosis is still bleak. Immunotherapies have transformed the treatment of a variety of cancers, and they provide great hope for glioblastoma, although they have yet to be successful. The justification for immune targeting of glioblastoma and the obstacles that come with treating these immunosuppressive tumors are reviewed in this paper. Cancer vaccines, oncolytic viruses (OVs), checkpoint blockade medications, adoptive cell transfer (ACT), chimeric antigen receptor (CAR) T-cells, and nanomedicine-based immunotherapies are among the novel immune-targeting therapies researched in glioblastoma. Key clinical trial outcomes and current trials for each method are presented from a clinical standpoint. Finally, constraints, whether biological or due to trial design, are discussed, along with solutions for overcoming them. In glioblastoma, proof of efficacy for immunotherapy approaches has yet to be demonstrated, but our rapidly growing understanding of the disease’s biology and immune microenvironment, as well as the emergence of novel promising combinatorial approaches, may allow researchers to finally meet the medical need for patients with glioblastoma multiforme (GBM).

Keeping up with venetoclax for leukemic malignancies: key findings, optimal regimens and clinical considerations

Introduction Venetoclax has transformed the treatment landscape in hematologic malignancies, especially in elderly population. With high rates of remission, deep and durable responses, and safe toxicity profile, venetoclax in combination therapy has been extremely effective, garnering accelerated approval and becoming standard of care in lymphoid and myeloid malignancies. Areas covered The role of venetoclax in the intrinsic apoptotic pathway is covered. This includes preclinical and clinical experience of venetoclax monotherapy and combination therapy in relapsed/refractory and frontline CLL, AML, ALL and high-risk MDS, with an emphasis on key clinical trials and efficacy of combination regimens in distinct mutational landscapes. Strategies to mitigate myelosuppression, manage dose adjustments and infectious complications are addressed. Expert opinion Targeting BCL-2 offers a safe and highly effective adjunct to available therapies in hematologic malignancies. Despite success and frequent utilization of venetoclax, several resistance mechanisms have been elucidated, prompting development of novel combinatorial strategies. Further, on-target myelosuppression of venetoclax is a key obstacle in clinical practice, requiring diligent monitoring and practice-based knowledge of dose modifications. Despite these limitations, venetoclax has gained tremendous popularity in hematologic-oncology, becoming an integral component of numerous combination regimes, with ongoing plethora of clinical trials encompassing standard chemotherapy, targeted agents and immune-based approaches.

Dosimetry in Clinical Radiopharmaceutical Therapy of Cancer: Practicality Versus Perfection in Current Practice.

The use of radiopharmaceutical therapies (RPTs) in the treatment of cancers is growing rapidly, with more agents becoming available for clinical use in last few years and many new RPTs being in development. Dosimetry assessment is critical for personalized RPT, insofar as administered activity should be assessed and optimized in order to maximize tumor-absorbed dose while keeping normal organs within defined safe dosages. However, many current clinical RPTs do not require patient-specific dosimetry based on current Food and Drug Administration-labeled approvals, and overall, dosimetry for RPT in clinical practice and trials is highly varied and underutilized. Several factors impede rigorous use of dosimetry, as compared with the more convenient and less resource-intensive practice of empiric dosing. We review various approaches to applying dosimetry for the assessment of activity in RPT and key clinical trials, the extent of dosimetry use, the relative pros and cons of dosimetry-based versus fixed activity, and practical limiting factors pertaining to current clinical practice.

Poly(ADP-Ribose) Polymerase Inhibition in Small Cell Lung Cancer: A Review.

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with high and rapid relapse rates and poor outcomes. Treatment for SCLC has historically been limited by the lack of targetable driver genomic lesions, however recent developments in the underpinnings of genomic instability in SCLC and understanding of its transcriptional subtypes have led to increased interest in the use of poly(ADP-ribose) polymerase (PARP) inhibitors as a rationale therapy. Poly(ADP-ribose) polymerase inhibitors, historically designed to target BRCA1/2-mutated malignancies, capitalize on synthetic lethality in homologous recombination-deficient tumors. In this review, we outline the mechanistic rationale for the use of PARP inhibitors in treating SCLC and detail key clinical trials investigating their use in combination with chemotherapy and immunotherapy. We describe developments in the understanding of biomarkers for sensitivity to therapy and highlight further investigational directions for the use of PARP inhibitors in treating SCLC.

Remote Delivery of Motor Function Assessment and Training for Clinical Trials in Neuromuscular Disease: A Response to the COVID-19 Global Pandemic.

Clinical outcome assessments of function or strength, assessed by physical therapists, are commonly used as primary endpoints in clinical trials, natural history studies and within clinics for individuals with neuromuscular disorders. These evaluations not only inform the efficacy of investigational agents in clinical trials, but also importantly track disease trajectory to prospectively advise need for equipment, home and work modifications, and other assistive devices. The COVID-19 pandemic had a global impact on the safety and feasibility of in-person visits and assessments, necessitating rapid development of mitigation strategies to ensure ongoing collection of key clinical trial endpoints and access to expert clinical care despite travel restrictions. Physical therapists who are expert in neuromuscular disorders working across clinics, countries, and clinical trials developed initial guidelines and methods for the suitability and feasibility of performing remote evaluations. A number of Sponsors introduced amendments to their study protocols to enable remote evaluations, supported by live video streaming of the assessment to their local clinical evaluators. Similarly, application of these techniques to clinical telemedicine enabled objective evaluations for use in payer discussions, equipment procurement, and general access to expert physical therapy services. Here we report on our methodology for adapting current practices to remote testing and considerations for remote evaluations.

Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer: Clinical and pathological perspectives.

Endometrial cancer is the most common gynecological cancer in developed countries, and its incidence has increased. The majority of patients with endometrial cancer have an early disease and favorable prognosis; however, a significant proportion of endometrial cancer, which mainly comprises high-grade or type II endometrial cancer such as serous, clear cell, and carcinosarcoma, shows advanced/recurrent disease and dismal prognosis. Novel therapeutic development is required for patients with aggressive endometrial cancers. Recent genomic and immunohistochemical analyses revealed human epidermal growth factor receptor 2 (HER2) overexpression/gene amplification in 20%-40% of patients with type II endometrial cancer. Historically, HER2 targeted therapy has been developed for various major cancers, including breast and gastric cancer. Notably, recent advances in HER2 targeted therapy for patients with type II endometrial cancer are also expected to change. Simultaneously, an optimized HER2 test for endometrial cancer as companion diagnostics should be established. In this review, we summarize the recent findings on endometrial cancer, current treatment, optimized HER2 testing, key clinical trials on HER2 targeted therapy, and future directions in aggressive endometrial cancer, including serous carcinoma and carcinosarcoma.

Set-up of GoLBeT, a pragmatic clinical trial of podoconiosis management in a low-resource setting

Abstract Clinical trials are often perceived as being expensive, difficult and beyond the capacity of academic groups and healthcare workers in low-resource settings. However, in order to improve healthcare coverage, the WHO World Health Report 2013 stated that all countries need to become generators as well as recipients of data. This study is a methodological examination of the steps and processes involved in setting up the Gojjam Lymphoedema Best Practice Trial (GoLBeT; ISRCTN67805210), a highly pragmatic clinical trial conducted in northern Ethiopia. Challenges to the trial and strategies used to deal with them were explored, together with reasons for delays. A qualitative approach using the Global Health Research Process Map as a framework was used to analyse emails and reports from the period between trial inception and recruitment. This analysis was complemented by interviews with key informants from the operational team and a group discussion. This study showed that the key areas of difficulty in setting up and planning this trial were: the study design (definition and measurement of the study endpoint, and assuring statistical power); recruitment and appropriate training of staff; planning for data quality; and gaining regulatory approvals. Collaboration was essential to successfully setting up the trial. Other important aspects were a team and process perspective, staff training, community engagement, and data quality e.g., through data management. Lessons learnt from this trial might guide in planning pragmatic trials in settings where research is not common, allowing researchers to anticipate challenges and address them through trial design, planning and operational delivery. We also hope that this example might encourage similar pragmatic studies to be undertaken. Such studies are rarely undertaken or locally led, but are an accessible and efficient way to drive improved outcomes in public health. Key messages Pragmatic clinical trials are essential to drive improved outcomes in public health in low-resource settings, but are perceived as challenging to set up and initiate. Our analysis of the Gojjam Lymphoedema Best Practice Trial found that factors for a successful set-up were collaborations, a team perspective, staff training, community engagement and data management.

1510 Percutaneous Coronary Intervention vs Coronary Artery Bypass Grafting in Left Main Coronary Artery Disease. A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract Aim There is still no consensus whether percutaneous coronary intervention (PCI) is as safe and effective as coronary artery bypass grafting (CABG) for left main coronary artery (LMCA) disease. Recent updates from key clinical trials necessitated an updated examination of the literature on this topic. Method A systematic search was performed of the MEDLINE (via PubMed), EMBASE, Cochrane and clinicaltrials.gov databases from inception to December 20th, 2020. Selected studies were analysed using the random effects model. Outcomes measured included all-cause mortality, MACCE, myocardial infarction (MI), stroke and revascularization. Follow up points were 30 days, 1 year, 5 years and 10 years. Results Six RCTs with a total population of 4700 were included in the analysis. For all-cause mortality PCI was non-inferior to CABG at all time points. MACCE favoured PCI at 30 days, and CABG at 5 years. No difference was seen at 1 year and 10 years. MI favoured CABG at 5 years follow up, with no difference seen at 30 days, 1 year or five years. For stroke, PCI was favourable to CABG at 30 days and 1 year, with no difference at 5 years and 10 years. Revascularisation favoured CABG at 1 year and 5 years, with no difference at other time-points. Conclusions PCI may be considered as an alternative to CABG for uncomplicated LMCA disease. More complex lesions may still benefit from CABG. CABG may be of benefit where future revascularisation would rather be avoided. Further clinical trials examining this research question are needed.

Improving CAR T-Cell Persistence.

Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

Recent clinical trials in atrial fibrillation.

Management of atrial fibrillation can be overwhelming with the amount of information and treatment options available today. This review discusses landmark and other clinically relevant trials published in the last 18 months. There have been several recent key clinical trials and subanalyses in the field of atrial fibrillation. Early rhythm control with ablation or antiarrhythmic medications has upended the previous practice of rate control for patients with atrial fibrillation. Vein of Marshall alcohol ablation in combination with endocardial mitral annular ablation and a hybrid epicardial/endocardial approach has shown promising results in the fight against persistent atrial fibrillation. Early ablation with cryoballoon therapy vs. antiarrhythmic therapy gives further evidence for early ablation in patients with symptomatic paroxysmal atrial fibrillation. The rapid development in technology and medications to treat atrial fibrillation, prevent stroke and improve quality of life for patients has created a vast amount of information for physicians to process. The present review will focus on the recent (within 2 years) clinical trials in atrial fibrillation and the impact they may have on your practice.

Blood Pressure Management After Endovascular Thrombectomy.

Endovascular thrombectomy (EVT) has changed the landscape of acute stroke therapy and has become the standard of care for selected patients presenting with anterior circulation large-vessel occlusion (LVO) stroke. Despite successful reperfusion, many patients with LVO stroke do not regain functional independence. Particularly, patients presenting with extremes of blood pressure (BP) or hemodynamic variability are found to have a worse clinical recovery, suggesting blood pressure optimization as a potential neuroprotective strategy. Current guidelines acknowledge the lack of randomized trials to evaluate the optimal hemodynamic management during the immediate post-stroke period. Following reperfusion, lower blood pressure targets may be warranted to prevent reperfusion injury and promote penumbral recovery, but adequate BP targets adjusted to individual patient factors such as degree of reperfusion, infarct size, and overall hemodynamic status remain undefined. This narrative review outlines the physiological mechanisms of BP control after EVT and summarizes key observational studies and clinical trials evaluating post-EVT BP targets. It also discusses novel treatment strategies and areas of future research that could aid in the determination of the optimal post-EVT blood pressure.

RadOnc Tables: An Online Resource for Commentary and Summaries of Key Clinical Trials

The RadOnc Tables key studies sheet and App aim to be a rapid online reference for key clinical trials in radiation oncology for a wide range of users, adapting features that are not possible in a physical book: continually up-to-date, updated in realtime, with fast usability, and crowd-sourcing of knowledge.

Clinical Utility of Olaparib in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Review of Current Evidence and Patient Selection.

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive and fatal disease with a median survival of 36 months. With the advent of genetic sequencing to identify individual genomic profiles and acquired tumor-specific pathways, targeted therapies have revolutionized cancer treatment, including the treatment strategy in mCRPC. Poly(adenosine 5ʹ-diphosphate) ribose polymerase inhibitors (PARPi) are oral drugs that target mutations in the homologous recombination repair (HRR) pathway, which are found in approximately 27% of prostate cancer patients. In May 2020, the first PARP inhibitor, olaparib, was approved by the US Food and Drug Administration for men with mCRPC with HHR gene mutations based on the findings of the Phase III PROfound trial that showed improved overall survival in men with mCRPC who received olaparib and whose disease had progressed on a novel hormonal agent. This review summarizes the current evidence and clinical utility of olaparib as treatment in men with mCRPC. We describe the mechanism of action of PARPi, key clinical trials of olaparib in men with mCRPC, and ongoing Phase II and III clinical trials investigating olaparib in combination therapy and as front-line therapy in mCRPC.