The Current Landscape of Treatment in Non-Metastatic Castration-Resistant Prostate Cancer.

Non-metastatic castration-resistant prostate cancer (nmCRPC) is a heterogeneous disease with variable potential in developing into overt metastases. It is an area of increased unmet need in advanced prostate cancer and for which there had been no great treatments until recent US Food and Drug Administration (FDA) approval of 2 novel anti-androgens apalutamide and enzalutamide, which were both approved given benefit in metastasis-free survival. Early data on the use of darolutamide, another novel anti-androgen, are also explored. This review discusses the pivotal trials that led to the approval of apalutamide and enzalutamide in the nmCRPC setting and discusses the key promises and challenges with the use of these agents.

Role of chemotherapy in prostate cancer.

Chemotherapy in prostate cancer (PCa) has undergone dramatic landscape changes. While earlier studies utilized varying chemotherapy regimens which were found to be largely palliative in nature and hardly resulted in durable or meaningful responses, docetaxel resulted in the first chemotherapy agent that showed improvement in overall survival in metastatic castration-resistant prostate cancer (mCRPC). However, combination chemotherapy or any agents added to docetaxel have failed to yield incremental benefits. The improvement in overall survival as well as secondary endpoints of prostate-specific antigen (PSA) and time to recurrence when using docetaxel in the metastatic hormone-sensitive state has changed the standard of care for treatment of newly diagnosed de novo metastatic PCa. There are also promising results in locally advanced PCa and high-risk PCa in both the neoadjuvant and adjuvant settings. This review summarizes the historical as well as the more contemporary use of chemotherapeutic agents in PCa in varying states and phases of disease.

Impact of abiraterone on patient-related outcomes in metastatic castration-resistant prostate cancer: current perspectives.

Abiraterone acetate has established a major role in the treatment paradigm of metastatic castration-resistant prostate cancer ever since pivotal trials, COU-AA-301 and COU-AA-302, have shown benefit in both the second-line and first-line (post- and pre-chemotherapy) setting, respectively, with improvement in overall survival as well as secondary end points such as prostate-specific antigen (PSA) and radiographic response rates, time to PSA progression, and progression-free survival. There has been a lot of interest and emphasis in the evaluation of patient-related outcomes (PROs) as it relates to quality of life, pain, adverse events, fatigue, and among others, in the use of different agents that have been shown to improve survival. This review examines the companion PROs in conjunction with abiraterone acetate use. This is particularly relevant since PROs are increasingly viewed as a key metric for drug label claims in granting approval across regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency.

Targeting Bone Metastases in Metastatic Castration-Resistant Prostate Cancer.

Skeletal involvement in metastatic castrate-resistant prostate cancer (mCRPC) is common and results in significant morbidity and mortality. The interaction of prostate cancer with the bone microenvironment contributes to progression of cancer in the bone leading to skeletal-related events (SREs). Studies aimed at targeting the bone have been carried out over the recent years. Bisphosphonates are synthetic pyrophosphate analogs first investigated for their role in SRE prevention with zoledronic acid as the main bisphosphonate that is approved by the US Food and Drug Administration for retardation of skeletal events in men with metastatic prostate cancer. Denosumab is another bone-targeted agent against uncontrolled osteolysis and serves as a RANK ligand inhibitor, superior to zoledronic acid in delaying SREs. Radiopharmaceuticals have played a role in targeting the bone microenvironment mainly in pain palliation in mCRPC utilizing strontium or samarium in the remote past, but only radium-223 is the first radiopharmaceutical that has yielded improvement in overall survival. The combination and sequencing strategies of these agents is the subject of multiple ongoing trials to guide the best use of these emerging agents.

Radium-223 for the treatment of castration-resistant prostate cancer.

The vast majority of patients with metastatic castration-resistant prostate cancer (mCRPC) develop bone metastases. Bone metastases are a source of significant morbidity and affect quality of life in these patients. Several bone-targeting agents are approved for the treatment of bone metastases in prostate cancer, including bisphosphonates, denosumab, and radiopharmaceuticals. Radium-223 is a novel first-in-class alpha-emitting radiopharmaceutical that has been approved for treatment of patients with mCRPC with bone metastases. Radium-223 delivers cytotoxic radiation to the sites of bone metastases and offers the advantage of minimal myelosuppression. The landmark Phase III ALSYMPCA trial demonstrated that, in addition to providing bone-related palliation, radium-223 can also prolong overall survival in patients with mCRPC with bone metastases in the absence of visceral metastases and in the absence of lymphadenopathy greater than 3 cm. Ongoing trials will further elucidate its use in sequence or combination with other available therapies for mCRPC.

Emerging therapies in multiple myeloma.

The treatment of multiple myeloma has evolved significantly over the past 2 decades due to the use of high-dose chemotherapy and autologous stem cell transplantation, and the subsequent introduction of the immunomodulatory agents (thalidomide and lenalidomide) and the proteasome inhibitor (bortezomib). The median overall survival of multiple myeloma patients has increased significantly with patients younger than age 50 years experiencing a 10-year survival rate of around 40%. However, despite the increased effectiveness of the first-line agents, the majority of patients will eventually relapse and become drug resistant. Promising novel therapies have recently emerged and are being used to treat relapsed and refractory patients. This review will cover the clinical data regarding these emergent therapies that include new generation of proteasome inhibitors (carfilzomib, ixazomib, oprozomib, and marizomib), immunomodulatory drugs (pomalidomide), monoclonal antibodies (elotuzumab and daratumumab), signal transduction modulator (perifosine), and histone deacetylase inhibitors (vorinostat and panobinostat).

Complications of allogeneic hematopoietic stem cell transplantation.

Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions.

Metastatic castration-resistant prostate cancer: critical review of enzalutamide.

Enzalutamide, previously known as MDV300, is an oral, second-generation androgen receptor (AR) signaling inhibitor or antagonist that was approved by the Food and Drug Administration in 2012 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) postdocetaxel. Preclinical studies have demonstrated impressive affinity to the AR compared to the first-generation AR inhibitors. The landmark Phase III AFFIRM trial demonstrated improved overall survival benefit compared to placebo in addition to improvement in all tested parameters. Enzalutamide is currently being studied in several trials prechemotherapy and in earlier settings of prostate cancer. This review will discuss the mechanism of action of enzalutamide, its pharmacokinetics, the preclinical and clinical trials that led to its approval, the ongoing clinical trials, its safety and efficacy, as well as patterns of resistance, and discusses its place in therapy within the context of several recently approved agents for mCRPC.

Bone-targeted therapies in metastatic castration-resistant prostate cancer: evolving paradigms.

Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone-targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC including strontium and samarium, alpharadin is the first radiopharmaceutical to show significant overall survival benefit. Contemporary therapeutic options including enzalutamide and abiraterone have effects on pain palliation and SREs as well. Other novel bone-targeted agents are currently in development, including the receptor tyrosine kinase inhibitors cabozantinib and dasatinib. Emerging therapeutics in mCRPC has resulted in great strides in preventing one of the most significant sources of complications of bone metastases.

The changing landscape in the treatment of metastatic castration-resistant prostate cancer.

The past few years have brought increasing advances in the therapeutic management of metastatic castration-resistant prostate cancer with the approval of several agents, including vaccine therapy with sipuleucel-T, second-line chemotherapy with cabazitaxel, the bone-targeted pharmaceutical denosumab, and the novel antiandrogen therapy abiraterone acetate. There are ongoing developments with other agents in the pipeline such as MDV3100 and alpharadin that have shown promising results. This review describes the clinical trials that brought about the drug approvals of various agents and offers some insights regarding a rational approach to optimal treatment sequencing for these drugs since national guidelines are currently lacking.