A Pilot Study of a Multimodal Treatment Paradigm to Accelerate Drug Evaluations in Early-stage Metastatic Prostate Cancer

Abstract

Objective: To evaluate a multimodal strategy aimed at treating all sites of disease that provides a rapid readout of success or failure in men presenting with non-castrate metastatic prostate cancers that are incurable with single modality therapy.

Materials and methods: Twenty selected men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis were treated using a multimodal approach that included androgen deprivation, radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease or the primary site. Outcomes of each treatment were assessed sequentially. Androgen deprivation was discontinued in responding patients. The primary end point was an undetectable prostate-specific antigen (PSA) after testosterone recovery. The goal was to eliminate all detectable disease.

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

Conclusion: A sequentially applied multimodal treatment strategy can eliminate detectable disease in selected patients with metastatic spread at diagnosis. The end point of undetectable PSA after testosterone recovery should be considered when evaluating new approaches to rapidly set priorities for large-scale testing in early metastatic disease states and to shift the paradigm from palliation to cure.

Figure 1

Individual PSA best absolute response by treatment modality (primary ADT, surgery, and radiation therapy) with best PSA response before next treatment is shown. Undetectable PSA values are highlighted. ADT, androgen deprivation therapy; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiation therapy.

Figure 2

Percentage of patients who achieved undetectable PSA during the treatment phase increased with each component of multimodal therapy. Response to treatment was assessed with serum PSA measurements, and the frequency of patients who achieved undetectable PSA after ADT alone, ADT + surgery, and ADT + surgery + radiation is shown. ADT, androgen deprivation therapy; M1a, extrapelvic nodal disease; M1b, bone metastasis; PSA, prostate-specific antigen.