Prostate cancer remains one of the leading causes of cancer death in men worldwide. In the past decade, several new treatments for advanced prostate cancer have been approved. With a wide variety of available drugs, including cytotoxic agents, androgen receptor axis-targeted therapies, and alpha-emitting radiation therapy, identifying their optimal sequencing remains a challenge. Progress in the understanding of the biology of prostate cancer has provided an opportunity for a more refined and personalized treatment selection process. With the advancement of molecular sequencing techniques, genomic precision through the identification of potential treatment targets and predictive biomarkers has been rapidly evolving. In this review, we discussed biomarker-driven treatments for advanced prostate cancer. First, we presented predictive biomarkers for established, global standard treatments for advanced diseases, such as chemotherapy and androgen receptor axis-targeted agents. We also discussed targeted agents with recent approval for special populations, such as poly ADP ribose polymerase (PARP) inhibitors in patients with metastatic castrate-resistant prostate cancer with homologous recombination repair-deficient tumors, pembrolizumab in patients with high levels of microsatellite instability or high tumor mutational burden, and prostate-specific membrane antigen (PSMA) directed radioligand theragnostic treatment for PSMA expressing tumors. Additionally, we discussed evolving treatments, such as cancer vaccines, chimeric antigen receptor T-cells (CAR-T), Bispecific T-cell engagers (BiTEs), other targeted agents such as AKT inhibitors, and various combination treatments. In summary, advances in molecular genetics have begun to propel personalized medicine forward in the management of advanced prostate cancer, allowing for a more precise, biomarker-driven treatment selection with the goal of improving overall efficacy.

While surgical resection has remained the mainstay of treatment in early-stage renal cell carcinoma (RCC), therapeutic options in the advanced setting have remarkably expanded over the last 20 years. Tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGF-TKIs) and anti-programmed cell death 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have become globally accepted options in the upfront metastatic setting, with different ICI-based combination strategies improving overall survival compared to single-agent Sunitinib. Although some patients benefit from long-term responses, most eventually develop disease progression. Ongoing efforts to better understand the biology of RCC and the different mechanisms of acquired resistance have led to the identification of promising therapeutic targets. Belzutifan, a novel agent targeting the angiogenic pathway involving hypoxia-inducible factors (HIFs), has already been approved for the treatment of early-stage tumors associated with VHL disease and represents a very promising therapy in advanced RCC. Other putative targets include epigenetic regulation enzymes, as well as several metabolites such as adenosine, glutaminase and tryptophan, which are critical players in cancer cell metabolism and in the tumor microenvironment. Different methods of immune regulation are also being investigated, including CAR-T cell therapy and modulation of the gut microbiome, in addition to novel agents targeting the interleukin-2 (IL-2) pathway. This review aims to highlight the emergent novel therapies for RCC and their respective completed and ongoing clinical trials.

Treatment of metastatic renal cell carcinomas (mRCC) has drastically improved since the advent of immunotherapy with immune checkpoint inhibitors (ICIs), with a significant proportion of patients achieving durable responses. While this has revolutionized treatment and improved outcomes for mRCC patients, a large subset of patients still does not respond to treatment with ICIs. Moreover, ICIs can induce various immune-related adverse events, limiting their use in many patients. Therefore, there is a need to identify the predictive biomarkers of both efficacy and toxicity associated with ICIs, which would allow for a more personalized approach and help with clinical decision-making. This review aims to explore the role of the gut microbiome in RCC to overcome primary resistance and predict response to treatment with ICIs. First, current therapeutic strategies and mechanisms of action of ICI therapies for RCC treatment will be reviewed. With the technological development of shotgun whole-genome sequencing, the gut microbiome has emerged as an exciting field of research within oncology. Thus, the role of the microbiome and its bidirectional interaction with ICIs and other drugs will be explored, with a particular focus on the microbiome profile in RCC. Lastly, the rationale for future clinical interventions to overcome resistance to ICIs using fecal microbiota transplantation in patients with RCC will be presented.

Aim: To evaluate optimal systemic therapy sequencing (first-line targeted therapy (1L-TT) vs. first-line immunotherapy (1L-IO)) in patients with BRAF-mutated metastatic melanoma. Methods: Nation-wide prospective data of patients with newly diagnosed BRAF-mutated metastatic melanoma were retrieved from the Canadian Melanoma Research Network. Results: Our study included 79 and 107 patients in the 1L-IO and 1L-TT groups, respectively. There were more patients with ECOG 0–1 (91% vs. 72%, p = 0.023) in the 1L-IO group compared to the 1L-TT group. Multivariable Cox analysis suggested no OS differences between the two groups (HR 0.838, 95%CI 0.502–1.400, p = 0.500). However, patients who received 1L-TT then 2L-IO had the longest OS compared to 1L-IO without 2L therapy, 1L-IO then 2L-TT, and 1L-TT without 2L therapy (38.3 vs. 32.2 vs. 16.9 vs. 6.3 months, p < 0.001). For patients who received 2L therapy, those who received 2L-IO had a trend towards OS improvement compared with the 2L-TT group (21.7 vs. 8.9 months, p = 0.053). Conclusions: Our nation-wide prospective study failed to establish any optimal systemic therapy sequencing in advanced BRAF-mutant melanoma patients. Nevertheless, we provided evidence that immunotherapy has durable efficacy in advanced BRAF-mutant melanoma patients, regardless of treatment line, and that Canadian medical oncologists were selecting the appropriate treatment sequences in a real-world setting, based on patients’ clinical and tumour characteristics.

Introduction: Radium-223 dichloride (radium-223) is a bone-targeting radioisotope therapy that aids in the survival of patients with metastatic castration-resistant prostate cancer (mCRPC) to bones. This study aimed to describe the clinical characteristics and outcomes of patients with mCRPC treated with radium-223 in a real-world setting. Methods: This was a retrospective study of patients with mCRPC treated with radium-223 between 2016 and 2020 at the London Health Sciences Centre in London, Canada. The baseline characteristics between the patients receiving 1–3 and 4–6 treatment cycles were compared using a two-sample t-test and Chi-square test. ANOVA was used to determine if there was a difference in each diagnostic variable per treatment cycle. Kaplan–Meier curves were generated to estimate progression-free survival (PFS) and overall survival in the patients treated with different numbers of cycles. Results: Fifty eligible patients were identified. The median age was 71 years (IQR: 66–76). Most patients (62%) received radium-223 beyond the third-line treatment. The mean number of radium-223 treatments was four. While 60% of the patients received 4–6 injections, 40% received 1–3 injections. Fifty-eight percent (58%) of the patients demonstrated a clinical benefit, with the remainder expressing either disease progression (28%) or stable disease (10%). The patients treated with 4–6 cycles had a delay to disease progression compared to those given 1–3 cycles of radium-223 (F_5,35 = 10.52, p < 0.001). A higher alkaline phosphatase level prior to treatment was associated with a longer PFS (z₃₃ = 2.362, p = 0.018). Treatment-related hospitalization for skeletal-related events was noted in 8% of the patients, and 14% required treatment discontinuation due to hematologic toxicity. Conclusions: This study confirms the safety of radium-223 in patients with mCRPC in a real-world setting. The radium-223 treatment was associated with a clinical benefit in the majority of the patients, particularly in those with higher pre-treatment serum alkaline phosphatase levels. Further studies to identify the predictive biomarkers are warranted to better guide the contemporary use of radium-223.