The burden of metastatic prostate cancer is likely to grow in the coming years. In 2018 there were approximately 1.3 million cases worldwide, with 20% of these patients having metastatic disease. Epidemiologic modeling suggests that the number of metastatic cases will rise with time, especially in the younger patient population (Aged 45-64). Fortunately, the field is doing better with regards to systemic therapy in metastatic disease, yet the majority of patients are not alive five years after their diagnosis. What are the ways then that we can improve outcomes in patients with metastatic disease, especially using multi-modality therapy?
One possibility is metastasis-directed therapy (MDT). There are multiple rationales for this approach as outlined by Dr. Vapiwala. One is a biological rationale, which argues that certain metastatic cases are biologically more indolent, providing a time window to address metastatic lesions and prevent the competitive outgrowth of potentially aggressive disease clones. It remains to be seen whether MDT overall changes disease outcomes, or if this succumbs to lead time bias from early detection of asymptomatic metastatic disease (as illustrated below). Importantly, the CHAARTED AND LATITUDE trials showed that not all metastatic cases are equal, offering hope that certain patients may ultimately live longer with their disease due to MDT.
Additional important rationales for MDT include patient-driven reasons (may help avoid growth of metastatic lesions that can cause symptoms, may help avoid toxicity from systemic therapy) and technological motivations (better imaging modalities to detect nodal and metastatic disease, the favorable alpha/beta ratio of prostate tissue that predisposes it to safe stereotactic ablative radiotherapy or SABR). But ultimately, these rationales must be supported by evidence.
Dr. Vapiwala then reviewed the available evidence in the area of MDT. She reviewed several pioneering case series that showed high rates of local control (95-100% at two years) with limited toxicity. Phase 2 studies have been a mix of randomized and single-arm studies with mixed enrollment criteria (various number of metastatic lesions), clinical states (some castration-sensitive, some castration-resistant), and endpoints (PFS versus therapy free survival). Notable larger studies in this space include SABR-COMET (Palma et al Lancet 2019), ORIOLE (Tran et al GU ASCO 2020), STOMP (Ost et al, JCO 2018 and updated 5-year results at GU ASCO 2020), POPSTAR (Siva et al, European Urology 2018), and TRANSFORM. Overall approximately 350 patients with recurrent prostate cancer have been enrolled in 5 prospective studies looking at MDT. These are summarized in the slide below, which overall indicates that MDT results in half of the patients being free of subsequent treatment after two years.
Multiple trials are open or planned in this space looking at various treatment contexts.
The available evidence suggests metastasis directed therapy is overall safe, feasible, and prolongs freedom from other treatment in a subset of patients. Continued assessment of genomic and clinical characteristics will hopefully further refine selection criteria for patients who are likely to respond to MDT.
Presented by: Neha Vapiwala, MD, Associate Professor of Radiation Oncology at the Hospital of the University of Pennsylvania
Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California