Dr. Boorjian began by highlighting the definition of biochemical recurrence, based on the AUA/ASTRO guidelines for adjuvant and salvage radiotherapy after prostatectomy. In this setting, biochemical recurrence (BCR) is defined as a detectable or rising PSA that is ≥0.2 ng/mL with a second confirmatory level that is also ≥0.2 ng/mL. While a variety of definitions of BCR have been used, this is optimal in terms of predicted five-year progression-free survival. However, when we consider the nuances of disease, a lower threshold may be appropriate for those with higher risk disease (eg. a single PSA ≥0.05 ng/mL). Following radiotherapy, a number of definitions of BCR have been used. Dr. Boorjian highlighted the Phoenix criteria of nadir PSA + ≥2 ng/mL. When considering the clinical actionability of a post-RT BCR, we need to consider whether the patient would be a candidate for salvage local therapy. If so, further investigation including MRI, prostate biopsy, and metastatic survey is appropriate.
Following surgery, Dr. Boorjian highlighted that the AUA/ASTRO guideline emphasizes the importance of informing patients that BCR is associated with a higher risk of developing metastatic disease and prostate cancer-related death. However, the natural history of BCR is heterogeneous and men with BCR remain as likely to die of something else in 15 years as they are to die of prostate cancer. Citing the classic Pound data, he emphasized that approximately one-third of patients with BCR develop metastasis without therapy with a median time of 8 years from BCR to metastasis and a further 5 years from metastasis to death. Citing data he published from the Mayo Clinic, Dr. Boorjian highlighted that the cancer-specific survival at 15 years following BCR is still 84%, though nearly one-quarter of this population received salvage therapy at BCR before systemic progression, unlike the Pound data. Salvage radiotherapy may, in these patients, significantly improve both cancer-specific and overall survival. Further, nomograms incorporating age, time to BCR, PSA doubling time, and pathologic characteristics may predict the risk of cancer-related mortality. On this basis, the EAU has defined BCR risk groups. These groups can stratify a patient’s risk of metastasis and mortality.
Again returning to the AUA/ASTRO guidelines, Dr. Boorjian emphasized the importance of postoperative radiotherapy being given when PSA levels are low. In relatively contemporary data, the five-year post salvage radiotherapy biochemical recurrence-free survival was strongly associated with PSA levels prior to salvage radiotherapy.
Dr. Boorjian then discussed the data regarding the addition of androgen deprivation therapy to salvage radiotherapy. In two randomized controlled trials, this has been shown to improve outcomes ranging from progression-free survival to death from prostate cancer and overall survival. Thus, such an approach should be offered for patients undergoing salvage radiotherapy according to the guidelines. However, in observational studies, the benefit of ADT in conjunction with early salvage RT appears to be limited to those with high-risk features including pT3b/4, Gleason grade group 4 or 5, and PSA at the initiation of salvage radiotherapy of 0.4 ng/mL or greater. Further, men with low PSA levels at the time of salvage radiotherapy may be harmed by the addition of ADT, with an increase in other-cause mortality.
However, more recent data suggest that the use of the Genomic Classifier may be able to stratify patients who benefit from the addition of ADT, based on a secondary analysis of the RTOG 9601 cohort. Men with a low GC score have little benefit and actually have worse overall survival when given ADT in this setting.
Dr. Boorjian then moved on to discuss the relatively recently published trials comparing adjuvant and early salvage radiotherapy, including RADICALS-RT and RAVES. Notably, adjuvant therapy was associated with worse urinary continence and increase urethral stricture disease but not improvements in five-year biochemical control. The pre-planned ARTISTIC meta-analyses of these data demonstrated no evidence that event-free survival is improved with adjuvant therapy as compared to early salvage radiotherapy. However, Dr. Boorjian noted that these data do not entirely preclude a role for adjuvant therapy given the eligibility criteria favoured patients at lower risk of recurrence. Indeed, a recently published observational study from Dr. Tilki and colleagues suggested a benefit to adjuvant therapy among those with adverse pathology while no benefit was seen among those without adverse pathology. Again, Dr. Boorjian cited data suggesting that biomarkers may assist with these decisions: the Genomic classifier was able to stratify those in whom adjuvant radiotherapy conferred a benefit in biochemical control, even among men with pT3b/4 disease, lymph node involvement, or Gleason score 8-10. However, the current AUA/ASTRO panel concludes that the present evidence is insufficient to discern whether these genomic classifiers can predict the efficacy of post-operative treatments.
Dr. Boorjian then moved on to discuss the role of salvage ADT for BCR after RP. He began citing observational data from Dr. Moul which showed no benefit to early ADT at the time of BCR compared to delayed ADT at the time of metastasis. However, in patients with Gleason score 8-10 or PSA doubling time less than 12 months, the early initiation of ADT delayed the development of clinically apparent metastasis. Two further studies showed no benefit in all-cause or prostate cancer-related mortality with the early initiation of ADT in large observational cohorts. The TOAD study assessed this in a prospective randomized fashion and found that immediate ADT was associated with a higher 5-year overall survival than delayed (>2 years) ADT (91% vs 86%) in patients with PSA relapse following predominately radiotherapy. Very recent data published in the Journal of Urology from the Johns Hopkins group showed that the median metastasis-free survival from biochemical recurrence without ADT treatment was 16 years and was 12 years even among those with PSA doubling time less than 6 months.
Returning to the AUA/ASTRO/SUO guidelines on advanced prostate cancer, he emphasized that observation or clinical trial enrollment are recommended for patients with rising PSA after the failure of local therapy without evidence of metastasis. ADT is not routinely indicated in this setting. However, the evaluation of these patients is evolving and the use of next-generation imaging may lead to earlier identification of disease.
Presented by: Stephen A. Boorjian, MD, Carl Rosen Professor of Urology, Vice Chair of Research, Department of Urology, Director, Urologic Oncology Fellowship, Mayo Clinic, Rochester, MN
Written by: Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto Contact: @WallisCJD on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.