Introduction

The paradigm of first testing systemic treatments in advanced disease followed by development in earlier disease states and finally large-scale trials evaluating whether the approach, in combination with local therapy, can prevent or delay the time-to-event measures of disease progression or death in patients with &[Prime]high-risk&[Prime] tumors is no longer practical now that 6 life-prolonging systemic therapies in metastatic castration-resistant prostate cancer are available. Our objective was to evaluate a multimodal treatment platform and a short term endpoint of treatment efficacy as a new strategy to rapidly evaluate and prioritize regimens for large-scale phase 3 testing.

Methods

We conducted a pilot study of twenty men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis. All sites of disease were treated using a multimodal approach that included androgen deprivation (ADT), radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease and/or the primary site. ADT was discontinued in responding patients. Outcomes of each treatment were assessed sequentially. The primary endpoint of &[Prime]no evidence of disease&[Prime] (NED) was defined by an undetectable PSA (<0.05 ng/mL) with noncastrate levels of testosterone at 20 months (>150 ng/dL).

Results

Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after ADT alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval 3-38%) achieved the primary endpoint, which persisted for 5, 6, 27+, and 46+ months. All patients meeting the primary endpoint had been classified with M1b disease at presentation

Conclusions

Treatment directed at all sites can eliminate detectable disease in selected patients with newly diagnosed metastatic prostate cancer. A multimodal treatment strategy inclusive of the NED endpoint for patients who present with disease that is beyond the limits of curability by any single modality should be considered to enable the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease.

Funding

The Sidney Kimmel Center for Prostate and Urologic Cancers, NIH/NCI P30 CA008748, NIH/NCI P50 CA092629, and David H. Koch Fund for Prostate Cancer Research