Mechanistic Insights on Localized to Metastatic Prostate Cancer Transition and Therapeutic Opportunities.

Prostate cancer is the most common non-cutaneous cancer among American men. Multiple mechanisms are involved in tumorigenesis and progression to metastases. While androgen deprivation therapy remains the cornerstone of treatment, progression to castration-resistant disease becomes inevitable. Aberrant pathway activations of PI3K/AKT due to PTEN loss, epithelial-mesenchymal transition pathways, homologous recombination repair, and DNA repair pathway mechanisms of resistance and cross-talk lead to opportunities for therapeutic targeting in metastatic castration-resistant prostate cancer. This review focuses on mechanisms of progression and key trials that evaluate the drugs and combinations that exploit these pathways.

The role of switch maintenance therapy in urothelial cancers.

Maintenance therapy with immune checkpoint inhibitors (ICIs) has changed the treatment paradigm of metastatic urothelial carcinoma (mUC). The JAVELIN Bladder 100 trial established avelumab, one of several ICIs in use today, as a life-prolonging maintenance therapy for patients with advanced urothelial carcinoma. Platinum-based chemotherapy is most often used in the first-line treatment of mUC, and while response rates approach about 50%, disease control is usually short-lived upon completion of the standard three to six cycles of chemotherapy. Much progress has been made in recent years in the second-line space and beyond with the use of ICIs, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs) in eligible patients at the time of disease progression post-platinum-based chemotherapy. However, many patients with progressive mUC after first-line chemotherapy suffer from rapid progression of disease, treatment toxicity with subsequent lines of therapy, and a limited life expectancy. Until the results of the JAVELIN Bladder 100 trial were presented in 2020, there were no maintenance strategies proven to be beneficial over best supportive care after disease control is achieved with first-line platinum-based chemotherapy. To date, standard of care frontline treatment of metastatic urothelial cancer remains to be four to six cycles of platinum-based chemotherapy followed by maintenance avelumab. This review summarizes the current evidence available on maintenance therapies in mUC, as well as several highly anticipated clinical trials that we hope will result in further progress in the management of this aggressive cancer and improve patient outcomes.

Non-urothelial and urothelial variants of bladder cancer.

Non-urothelial bladder cancers make up a rare minority of all genitourinary (GU) tract histologic cancers since urothelial cancer (UC) makes up the most common histologic subtype. Bladder cancer variant histology (BCVH) or urothelial variants also occur rarely though distinction is important given aggressive presentation and natural history. While methods for diagnosis and treatment of typical urothelial cancers (UC) are well-established, there are no clear guidelines with regard to the diagnosis of non-urothelial bladder cancers, which often results in misdiagnosis and treatment delay. This review will focus on the clinicopathologic characteristics of the most common non-urothelial bladder cancers, to be distinguished from bladder cancer variant histology containing a UC component. The role of genomics in non-urothelial bladder cancers is evolving and the use of biomarkers to guide the diagnosis and treatment of these tumors remains a key area of unmet need. Treatment of these cancers will be discussed in a companion review.

Advances with androgen deprivation therapy for prostate cancer.

INTRODUCTION: Androgen deprivation therapy (ADT) has been a treatment of choice for prostate cancer in almost all phases, particularly in the locally advanced, metastatic setting in both hormone-sensitive and castration-resistant diseaseand in those who are unfit for any local therapy. Different ways of administering ADT comes in the form of surgical or chemical castration with the use of gonadotropin-releasing hormone (GnRH-agonists) being the foremost way of delivering ADT. AREAS COVERED: This review encompasses ADT history, use of leuprolide, degarelix, and relugolix, with contextual use of ADT in combination with androgen-signaling inhibitors and potential mechanisms of resistance. Novel approaches with regard to hormone therapy are also discussed. EXPERT OPINION: The use of GnRH-agonists and GnRH-antagonists yields efficacy that is likely equivalent in resulting in testosterone suppression. While the side-effect profile with ADT are generally equivalent, effects on cardiovascular morbidity may be improved with the use of oral relugolix though this is noted with caution since the cardiovascular side-effects were a result of secondary subgroup analyses. The choice of ADT hinges upon cost, availability, ease of administration, and preference amongst physicians and patients alike.

A Contemporary Review of Immune Checkpoint Inhibitors in Advanced Clear Cell Renal Cell Carcinoma.

The use of checkpoint inhibitors in advanced and metastatic renal cell carcinomas (RCCs) has rapidly evolved over the past several years. While immune-oncology (IO) drug therapy has been successful at resulting in improved responses and survival, combination therapies with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors have further improved outcomes. This article reviews the landmark trials that have led to the approval of IO therapies, including the Checkmate 214 trial and combination IO/VEGF TKI therapies with Checkmate 9ER, CLEAR, and Keynote-426, and it includes a discussion on promising therapies moving in the future.

Chronic Lymphocytic Leukemia: Current Concepts.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, and while in early, asymptomatic stages treatment is not indicated, the threat to the quality of life and increased mortality of patients posed by more advanced-stage disease necessitate therapeutic intervention. Guidelines of when and how to treat are not well-established because CLL is a disease of the elderly and it is important to balance preservation of functional status and control of the disease. Advances in molecular and genetic profiling has led to the ability to identify sub-groups of patients with CLL whose disease may respond to selected therapy. This review discusses current standard therapies in the major sub-groups of CLL based on age and functional status, in both the front-line and relapsed/refractory settings. It also provides a concise review of novel agents that have shown considerable efficacy in CLL.

Granulocytic sarcoma in a patient with chronic myeloid leukaemia in complete haematological, cytogenetic and molecular remission.

Granulocytic sarcoma, also known as myeloid sarcoma, is an extramedullary tumour composed of immature myeloid cells. Granulocytic sarcoma is typically found in patients with acute myeloid leukaemia, accelerated phase or blast crisis of chronic myeloid leukaemia, myelodysplastic syndrome, or as an isolated event without bone marrow involvement. We present a case of granulocytic sarcoma in a patient with chronic myeloid leukaemia in the setting of complete haematological, molecular and cytogenetic remission. Our patient was first treated with imatinib for chronic-phase chronic myeloid leukaemia. After maintaining remission for 42 months, he developed a granulocytic sarcoma in his spine. In this case report, we describe our case, along with the three other cases reported in the literature. In addition to being a rare diagnosis, this case demonstrates the importance of being vigilant in diagnosing the cause of back pain and atypical symptoms in patients with a history of leukaemia.

4-1BB-based isolation and expansion of CD8+ T cells specific for self-tumor and non-self-tumor antigens for adoptive T-cell therapy.

Adoptive T-cell therapy is a promising approach to the immunotherapy of cancer, but for it to be a general cancer therapy a simple and standardized procedure for producing tumor-specific CD8 T cells is needed. On the basis of a unique property of 4-1BB (CD137), the selective expression on activated T cells, we have developed a simple and practical protocol to produce antigen-specific CD8 T cells from peripheral blood mononuclear cells. We have proved the feasibility of this procedure by isolating and expanding cytomegalovirus-specific CD8 T cells, and applied the procedure to produce Epstein-Barr virus (EBV)-specific CD8 T cells. By using this procedure, we could readily produce 10-10 antigen-specific CD8 T cells from 30 to 50 mL of blood in about 4 weeks. Moreover, our protocol allowed us to produce, from solid cancer patients, CD8 T cells that were specific for self/tumor antigens such as human telomerase reverse transcriptase (hTERT). It is interesting to note that, we were unable to amplify hTERT-specific CD8 T cells from healthy donors. Our protocol can be readily translated into cGMP-compliant production and is currently being used to produce EBV-specific CD8 T cells for phase I clinical trial. We believe that our method will provide a practical and effective option for adoptive T-cell therapy in the clinic.

Angiogenesis inhibitors in prostate cancer therapy.

Limited treatment options exist for metastatic castrate-resistant prostate cancer (mCRPC). The concept of targeting tumors via anti-angiogenic mechanisms has been studied over the last decade, giving rise to a new class of anti-cancer drugs. Currently, the use of angiogenesis inhibition in prostate cancer is the focus of many ongoing clinical trials, with tumor progression and overall survival established as outcome measures. Several anti-angiogenic agents are currently under investigation with varying mechanisms by which they exert activity against prostate tumors. We describe the significant findings and outcomes of clinical trials involving the use of these drugs in mCRPC patients, along with how these results will translate to their use in the clinical setting. Open interventional trials that are currently recruiting participants are also mentioned. While the use of angiogenesis inhibition holds promise in the treatment of prostate cancer, several challenges still exist. The foreseeable clinical implications and limitations of anti-angiogenic therapy and the potential use of biomarkers are hereby discussed.

The use of 5-alpha reductase inhibitors for the prevention of prostate cancer.

The use of 5-alpha-reductase inhibitors has been studied not only in benign prostatic hyperplasia, but as a chemopreventive strategy in prostate cancer. Both finasteride and dutasteride, 5 alpha-reductase inhibitors (5ARI), have been shown to decrease the risk of prostate cancer. The results of the REDUCE trial using the dual alpha-reductase isoenzyme inhibitor dutasteride, has recently been published by Andriole et al. in the New England Journal of Medicine. Certain considerations regarding its use and applicability to men with high risk of developing prostate cancer are herein discussed.