Chapter 54 - Castration Resistant Prostate Cancer: Role of Chemotherapy

The last decade brought many new treatment options that changed the treatment algorithms for metastatic castrate-resistant prostate cancer (mCRPC). One of the most challenging tasks today is the optimal sequencing of agents since timing and patient selection are crucial to maximizing the therapeutic benefit. Docetaxel plays an important role in prostate cancer management and is likely to remain the same given the dramatic survival advantage in patients with newly diagnosed metastatic disease. A few phase III studies are currently testing the role of cabazitaxel as a frontline chemotherapy. Cleary, more research is needed to refine our understanding of predictors of response that will hopefully answer the question of how to sequence available treatments in order to maximize survival advantage. Discovery of predictive biomarkers has become one of the top priorities in prostate cancer research

Current Management Strategy for Metastatic Renal Cell Carcinoma and Future Directions

Purpose of Review Major strides have been made in the treatment of kidney cancer in the last several years with checkpoint immunotherapies and novel targeted agents. This manuscript will review current treatment strategies for metastatic renal cell carcinoma and will discuss future directions. Recent Findings Most recently, several new drugs including nivolumab, cabozantinib, and a combination of lenvatinib and everolimus have demonstrated acceptable toxicity and significantly improved overall survival, but evidence-based guidelines for sequencing of the approved treatment options and treatment selection based on biomarkers are still missing. Summary Despite the significant progress, many questions still remain unanswered. Several ongoing clinical trials are evaluating sequencing, timing of cytoreductive nephrectomy, combinations of immunotherapies and targeted therapies as well as selection of the best systemic treatment. Personalized treatment based on tumor profiling is one of the brightest spots on the horizon

Current Management Strategy for Metastatic Renal Cell Carcinoma and Future Directions.

PURPOSE OF REVIEW: Major strides have been made in the treatment of kidney cancer in the last several years with checkpoint immunotherapies and novel targeted agents. This manuscript will review current treatment strategies for metastatic renal cell carcinoma and will discuss future directions. RECENT FINDINGS: Most recently, several new drugs including nivolumab, cabozantinib, and a combination of lenvatinib and everolimus have demonstrated acceptable toxicity and significantly improved overall survival, but evidence-based guidelines for sequencing of the approved treatment options and treatment selection based on biomarkers are still missing. Despite the significant progress, many questions still remain unanswered. Several ongoing clinical trials are evaluating sequencing, timing of cytoreductive nephrectomy, combinations of immunotherapies and targeted therapies as well as selection of the best systemic treatment. Personalized treatment based on tumor profiling is one of the brightest spots on the horizon

Pembrolizumab in Combination with Axitinib as First-Line Treatment for Patients with Renal Cell Carcinoma (RCC): Evidence to Date

Over the last 18 months, 3 immunotherapy combination regimens (ipilimumab + nivolumab, pembrolizumab + axitinib, and axitinib + avelumab) were approved by the US Food and Drug Administration for the first-line treatment of metastatic renal cell carcinoma (mRCC), making selection of the optimal first-line treatment regimen very challenging. As of April 2020, preferred first-line treatment options for mRCC are pembrolizumab + axitinib and ipilimumab + nivolumab, based on the improvement in overall survival and progression-free survival compared to sunitinib, as observed in pivotal phase III clinical trials. Because the combination of 2 drugs is typically more toxic than a monotherapy, careful attention must be given to overlapping toxicities. The pembrolizumab + axitinib combination led to grade >= 3 adverse events in 75.8% of patients (vs 70.6% in the sunitinib group), while grade >= 3 adverse events were less frequent in the nivolumab + ipilimumab group compared to the sunitinib group. Discontinuation rates due to toxicity were 10.7% for pembrolizumab + axitinib (both drugs), 22% for ipilimumab + nivolumab and were comparable with sunitinib in both studies (13.9% and 12%, respectively). The combination of pembrolizumab + axitinib may have immune-modulating functions that may provide clinical benefit without the additional toxicity observed with ipilimumab + nivolumab. In addition, this tyrosine kinase inhibitor + immune checkpoint combination should have faster treatment response in patients with larger disease burden or in more symptomatic patients, which makes this combination an excellent choice for the first-line treatment regimen for mRCC. These combinations have proven to be tolerable, though long-term results are still lacking. As treatment options for mRCC are rapidly expanding, immunotherapy combinations could potentially change the treatment paradigm, with the ultimate goal of prolonging life and eventually curing mRCC

Cancer Vaccines

Cancer vaccines are a promising strategic approach within the rapidly growing field of immuno-oncology. Therapeutic cancer vaccines are distinct from prophylactic vaccines and vary by both target antigen and vaccine platform. There are currently 3 FDA-approved therapeutic cancer vaccines: intravesical BCG live, sipuleucel-T, and T-VEC. Prior clinical trials have shown that vaccines are generally well tolerated, exhibit unique kinetics, can target tumor neoantigens, and induce antigen cascade. Ongoing clinical trials seek to improve vaccine efficacy either by targeting novel antigens or by combining vaccines with standard-of-care therapies or other immune therapies

Endpoints, patient selection, and biomarkers in the design of clinical trials for cancer vaccines

Therapeutic cancer vaccines are an emerging and potentially effective treatment modality. Cancer vaccines are usually very well tolerated, with minimal toxicity compared with chemotherapy. Unlike conventional cytotoxic therapies, immunotherapy does not result in immediate tumor shrinkage but may alter growth rate and thus prolong survival. Multiple randomized controlled trials of various immunotherapeutic agents have shown a delayed separation in Kaplan-Meier survival curves, with no evidence of clinical benefit within the first 6-12 months of vaccine treatment. Overall survival benefit is seen in patients with lower disease burden who are not expected to die within those initial 6-12 months. The concept of improved overall survival without marked initial tumor reduction represents a significant shift from the current paradigms established by standard cytotoxic therapies. Future clinical studies of therapeutic vaccines should enroll patients with either lower tumor burden, more indolent disease or both, and must seek to identify early markers of clinical benefit that may correlate with survival. Until then, improved overall survival is the only clear, discriminatory endpoint for therapeutic vaccines as monotherapies