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The diagnostic and treatment landscape for patients with advanced prostate cancer has been expanding in recent years. Advanced diagnostics for disease detection, molecular-based biomarkers to inform therapeutic decisions, and targeted and novel agents have now populated the arena, shifting practice patterns and the clinical management of advanced prostate cancer.

While these new advances and therapeutics are promising to optimize the care of patients with advanced prostate cancer, many questions remain regarding clinical integration into routine practice.

In a recent article in , Mar and colleagues present an overview of current challenging clinical scenarios in the modern care of patients with advanced prostate cancer. The review presents answers, using the current body of evidence, to challenging clinical questions that are encountered by physicians and multidisciplinary practices on a daily basis.

The key questions addressed resolved around:

• The role of biomarkers to guide therapy selection for patients

• Timing of treatment initiation for men with biochemically recurrent prostate cancer

• Systemic and local therapy approaches to low- and high-volume metastatic castration-sensitive prostate cancer

• Timing and type of systemic therapy for non-metastatic castration-resistant prostate cancer

• Sequencing of systemic therapies and novel approaches for men with metastatic castration-resistant prostate cancer

In clinical practice, current biomarkers used to inform therapy selection for patients with advanced disease include the presence of homologous recombination repair alterations, though differential outcomes have been observed by type of alteration, microsatellite instability/mismatch repair deficiency, and high tumor mutation burden.

Other candidate biomarkers are currently under investigation, including PTEN loss and CDK12 loss, as we herald into the precision medicine era in prostate cancer.

Biochemically recurrent prostate cancer can be challenging, given the lack of clear consensus regarding the timing and type of systemic therapy. Current data does not demonstrate a clear advantage to early or continuous androgen-deprivation therapy, though many caveats, such as disease risk factors and patient goals for care, need to be considered when initiating treatment.

Several large phase III trials have recently transformed our clinical approach to the management of metastatic castration-sensitive prostate cancer. Collectively, these data demonstrate that the addition of either androgen receptor signaling pathway inhibitors or docetaxel chemotherapy improves outcomes for patients when added to androgen-deprivation therapy and should be discussed with patients.

Evolving data also support the role of prostate-directed radiation therapy for patients with low-volume disease. While data are robust for use of androgen receptor signaling pathway inhibitors for both low- and high-volume disease, use of chemotherapy for low-volume metastatic hormone-sensitive prostate cancer has shown mixed results.

In the context of non-metastatic castration-resistant prostate cancer, three next-generation anti-androgens have now demonstrated improvement in metastatic-free survival and overall survival compared with androgen deprivation alone and should be considered for men with high-risk non-metastatic castration-resistant prostate cancer.

Next-generation imaging, including PET and multiparametric MRI, have enhanced detection of metastatic disease at lower PSA levels, resulting in questions regarding the optimal management of clinical disease states in which metastases are not seen on standard imaging but are detected on next-generation imaging. Furthermore, the role of metastasis-directed therapy and systemic therapy for men with oligometastatic prostate cancer is still evolving.

Lastly, metastatic castration-resistant prostate cancer remains a lethal disease and new approaches need to be considered for overcoming resistance and prolonging survival.

Multiple radiopharmaceuticals are currently under investigation and hold promise for improving outcomes for patients. Additional novel approaches include bipolar androgen-deprivation therapy and novel targeted and immunotherapy combinations.

In aggregate, the advances in the field of prostate cancer have been tremendous over the past several years. However, we need to continue to strive to answer lingering clinical questions to ensure that men with prostate cancer are living longer and better.

Rana R. McKay, MD, is associate professor of medicine and co-leader of the Genitourinary Oncology Disease Team at the University of California San Diego, Moore Cancer Center, in La Jolla.

Read the study here and an interview about it here.