The 2023 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between June 2nd and June 6th was host to a prostate, testicular, and penile cancers oral abstract session. Dr. Praful Ravi presented the results of an individual patient data meta-analysis of randomized trial from the ICECaP collaboration evaluating the prognostic impact of a PSA nadir ≥0.1 ng/mL within 6 months of completion of radiotherapy for localized prostate cancer.
Radiotherapy plus androgen deprivation therapy (ADT) is a standard of care approach for the treatment of patients with intermediate or high-risk prostate cancer. The development of surrogate measures of metastasis-free survival (MFS) and overall survival (OS) could help in trial designs to evaluate new systemic therapies with ADT and radiotherapy. Previous studies have demonstrated that a PSA of >0.1 ng/ml or >0.5 ng/ml following neoadjuvant ADT and after 3-6 months of radiotherapy completion, respectively, are prognostic of worse survival outcomes in both retrospective and prospective studies.1-3
ICECaP (Intermediate Clinical Endpoints in Cancer of the Prostate) collects individual patient data from >40 randomized trials in localized prostate cancer (both radical prostatectomy- and radiotherapy-based) between 1987 and 2016. This group has previously established the surrogacy of MFS for OS in localized prostate cancer, which has important implications for both trial design and interpretation of currently available data.4
In this study, the investigators utilized the available data from the ICECaP individual patient data repository to evaluate the prognostic impact of PSA levels 6 months post-completion of radiotherapy on MFS, prostate cancer-specific mortality (PCSM), and OS. This analysis included patients receiving radiotherapy alone, radiotherapy plus short-term ADT (3-6 months), and radiotherapy plus long-term ADT (24-36 months). The investigators recorded the lowest PSA value within 6 months of radiotherapy completion. A cut-off of 0.1 ng/ml was chosen to reflect the lower limit of assay detection in the era during which the included trials were conducted. The investigators utilized multivariable Cox proportional hazard modeling to evaluate the association of PSA <0.1 ng/ml on the endpoint of MFS and OS. Conversely, Fine and Gray modeling, accounting for the competing risk of non-prostate cancer-related morality, was used for PCSM. The multivariable models were adjusted for age, ECOG performance status, T-stage, and Gleason Score.
This analysis included a total of 10,415 patients from 16 trials, with a median follow-up of 10.1 years.
The baseline patient characteristics in the overall cohort and by treatment group are summarized below. Dr. Ravi noted that the majority of patients (66%) were randomized prior to the year 2000. 30% of patients in the radiotherapy alone group were NCCN high risk, which is not consistent with current standard of care practice. The median PSA at randomization was highest in the radiotherapy + long-term ADT group (18.8 ng.ml versus 10.1 to 13.9 ng/ml).
The median lowest PSA at any time after randomization was 0.5 ng/ml in the radiotherapy only group, compared to 0.1 in both of the radiotherapy + ADT groups. The median time to lowest PSA was also prolonged in the radiotherapy alone group (23 months versus 5 and 7 months, respectively).
As demonstrated in the summary table below, a 6-month PSA level ≥0.1 ng/ml was associated with significantly worse 5-year MFS, 10-year OS, and 10-year PCSM, on univariable analysis, in all three treatment groups.
This is further supported by results presented in the forest plot below, which consistently show that a PSA level ≥0.1 ng/ml is associated with worse MFS, PCSM, and OS on multivariable analysis (statistical significance not reached for certain comparisons due to limited power from small sub-sample sizes and number of events).
Dr. Ravi highlighted that this is the largest assessment of the impact of PSA 6 months after radiotherapy completion in patients receiving radiotherapy or radiotherapy plus ADT for localized prostate cancer. These results demonstrated that a 6-month PSA level ≥0.1 ng/ml following radiotherapy completion is strongly prognostic for MFS, PCSM, and OS in patients receiving radiotherapy either alone or in combination with ADT. These findings have important implications for trial design with patients having a PSA level ≥0.1 ng/ml potential candidates for treatment escalation, whereas those with a level <0.1 ng/ml may be candidates for treatment de-escalation.
This study is strengthened by the availability of individual patient data from randomized trials. This is the largest individual patient data evaluation to date of the prognostic impact of landmark PSA (for both radiotherapy and radiotherapy plus ADT). This study further demonstrates a robust association of 6-months PSA with all three long-term outcome measures. This study is limited by the small sample size for radiotherapy only patients achieving a PSA <0.1 ng/ml. The investigators could not evaluate trial-level surrogacy and, as such, future work is needed. Furthermore, most men were treated prior to 2000 and this analysis includes studies across a wide span of “treatment eras”.
Dr. Ravi concluded that:
- PSA ≥0.1 ng/ml within 6 months of radiotherapy completion is highly prognostic for MFS, PCSM, and OS in men receiving radiotherapy +/- ADT for localized prostate cancer
- These results aid in counselling of patients treated with radiotherapy +/- ADT in routine practice
- These results have implications for adjuvant trial designs evaluating novel systemic therapies with radiotherapy + ADT or intensification/de-intensification approaches
Presented by: Praful Ravi, MRCP, MBBChir, Instructor in Medicine, Dana-Farber Cancer Institute, Boston, MA
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.References:
- D’Amico et al. Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two randomised trials. Lancet Oncol, 2012.
- Naik et al. Posttreatment Prostate-Specific Antigen 6 Months After Radiation With Androgen Deprivation Therapy Predicts for Distant Metastasis–Free Survival and Prostate Cancer–Specific Mortality. IJBROBP, 2016.
- Bryant et al. Cancer, 2018.
- Xie et al. Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer. J Clinc Oncol, 2017.