SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.
The ASCO clinical practice guideline published in 2018, recommended the addition of either TAXOTERE® (Docetaxel) or ZYTIGA® (Abiraterone acetate) to ADT, based on CHAARTED trial and STAMPEDE/LATITUDE trials respectively, for men with newly diagnosed metastatic Prostate cancer, based on the Overall Survival benefit with these combinations, when compared with the use of ADT alone. It is also well established that the addition of Radiation Therapy (RT) to Androgen Deprivation Therapy (ADT) improves Overall Survival compared to ADT alone, in patients with locally advanced Prostate cancer. Patients with metastatic Prostate cancer however are often treated with systemic therapy alone without any local intervention such as Radiation Therapy to the Prostate gland.
The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial is an ongoing phase III study and uses a novel multi-arm, multi-stage (MAMS) platform design, to test whether the addition of further treatments to ADT improves Overall Survival, when used in first-line setting, for patients with hormone sensitive, locally advanced or metastatic Prostate cancer. This group previously reported that there was a significantly improved Overall Survival with the addition of TAXOTERE® to initial ADT and also concluded that ZYTIGA® and prednisolone along with ADT results in significantly higher rates of Overall Survival as well as Failure-Free Survival, compared with ADT alone, among men with hormone sensitive, locally advanced or metastatic Prostate cancer.
The authors in this study had hypothesized based on studies in animal models that local treatment of the Prostate might not only improve local control but also slow progression of metastatic disease and improve Overall Survival in men presenting with metastatic Prostate cancer, and that survival benefit would be greater in men with lower metastatic burden. The accompanying results are from a preplanned analysis of one group in the multi-arm, multi-stage STAMPEDE study.
The study included 2,061 patients with newly diagnosed metastatic Prostate cancer who were randomized 1:1 to Standard of Care treatment consisting of lifelong Androgen Deprivation Therapy with or without early TAXOTERE® or the same Standard of Care plus Radiation Therapy to the Prostate. Radiotherapy was administered in two different schedules – either daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in 6 fractions for 6 weeks) based on investigator’s choice. The median age was 68 years, the median PSA level was 97 ng/mL and 18% received early TAXOTERE® treatment at the investigator’s discretion. Metastatic disease burden was characterized as Low in 40% and High in 54% and 6% was unknown. A High Prostate cancer disease burden was defined as 4 or more bone metastases, with at least 1 metastasis outside the axial skeleton and/or visceral metastases. The rest of the patients were characterized as having Low disease burden. The Primary outcome measure was Overall Survival and Secondary outcomes included Failure-Free Survival (FFS), and toxicity.
It was noted that Radiation Therapy to the Prostate improved FFS (HR=0.76; P<0.001) but not Overall Survival. However subgroup analysis showed that Radiation Therapy to the Prostate improved Overall Survival by 32% in the 819 men with lower metastatic disease burden (HR=0.68) and the 3 year Overall Survival rates were 81% in the Radiation Therapy arm versus 73% for Standard of Care, suggesting an absolute benefit of 8% and this was statistically significant (P =0 .007). By contrast, the 1120 men with higher metastatic disease burden did not benefit from Radiation Therapy. The Radiation Therapy schedule did not have any impact on outcomes. Radiation Therapy to the Prostate was well tolerated, with 5% of patients experiencing grade 3 or 4 adverse events during treatment and 4%, after treatment.
It was concluded that Prostate Radiotherapy in addition to systemic drug therapy improves the Overall Survival of men with newly diagnosed metastatic Prostate cancer who have a low metastatic disease burden, and should now be a standard treatment option. The authors added that this study did not include patients with pelvic node-positive nonmetastatic disease (N1, M0), where the addition of Radiotherapy to systemic drug therapy could be curative. Radiotherapy (RT) to the primary tumour for men with newly diagnosed metastatic prostate cancer (PCa): survival results from STAMPEDE (NCT00268476). Parker CC, James ND, Brawley C, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA5.