ASCO 2022: Salvage Treatment for Biochemical Recurrence After Radical Prostatectomy

(UroToday.com) The 2022 ASCO meeting included a session on the best approaches and updates for prostate cancer biochemical recurrence, including a presentation by Dr. Chris Parker discussing salvage treatment for biochemical failure after radical prostatectomy. According to Dr. Parker, there are four discussion points with regards to salvage treatment for biochemical failure after radical prostatectomy: (i) salvage radiotherapy dose, (ii) salvage radiotherapy target volume, (iii) use of ADT with salvage radiotherapy, and (iv) timing of salvage radiotherapy.

With regards to salvage radiotherapy dose, Dr. Parker notes that in a study by Tendulkar et al.1 assessing a contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy, prostate bed radiotherapy dose (>= 6,600 cGy vs <6,600) had a minor role in the proposed nomogram:

 

ASCO 2022_Chris C. Parker_Salvage Treatment_0 

 

 Furthermore, Dr. Parker notes that the SAKK 09/10 trial aimed to compare conventional and dose-intensified salvage radiotherapy, randomizing patients to conventional-dose (64 Gy) or dose-intensified salvage radiotherapy (70 Gy) to the prostate bed without hormonal therapy. After median follow-up of 6.2 years, the median freedom from biochemical recurrence was 8.2 years in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% CI 0.82-1.60). Dr. Parker notes that this result is not that surprising, given that in this setting radiotherapy is treating micrometastatic disease and these doses are not that different.

With regards to salvage radiotherapy target volume, Dr. Parker notes that his group recently assessed their group’s pattern of failure after prostate bed radiotherapy, noting a particularly high rate of pelvic nodal recurrence:

 

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 More recent evidence has come from the RTOG 0534 SPPORT trial assessing the addition of ADT and pelvic lymph node treatment to prostate bed salvage radiotherapy.3 Eligible patients for this trial were those who after prostatectomy had a persistently detectable or an initially undetectable and rising PSA of between 0.1 and 2.0 ng/mL. Patients were randomly assigned to receive prostate bed radiotherapy alone at a dose of 64.8-70.2 Gy at 1.8 Gy per fraction daily (group 1), prostate bed radiotherapy plus short-term ADT (group 2), or pelvic lymph node radiotherapy (45 Gy at 1.8 Gy per fraction) plus prostate bed radiotherapy plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. Among 1,792 patients randomized to the three groups, 1,716 patients were evaluable. At a median follow-up among survivors of 8.2 years (IQR 6.6-9.4), the 5-year freedom from progression rates were 70.9% (95% CI 67.0-74.9) in group 1, 81.3% (78.0-84.6) in group 2, and 87.4% (84.7-90.2) in group 3:

 

ASCO 2022_Chris C. Parker_Salvage Treatment_2 

 

 With regards to use of ADT with salvage ADT, the only randomized trial in this setting to date was published by Shipley et al.4 assessing whether antiandrogen therapy with radiation therapy improves cancer control and prolong OS among patients with biochemical recurrence. In this RTOG 9601 trial there were 760 patients who had undergone radical prostatectomy with a lymphadenectomy and had biochemically recurrent disease who were randomized to radiation therapy and to receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the OS rate and the actuarial rate of OS at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (HR 0.77, 95% CI 0.59 to 0.99). The 12-year incidence of death from prostate cancer was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (p < 0.001):

 

ASCO 2022_Chris C. Parker_Salvage Treatment_3 

 

 Feng and colleagues validated the Decipher genomic classifier in patients with recurrent prostate cancer using data from the RTOG 9601 randomized clinical trial.5 On multivariable analysis, the genomic classifier was independently associated with distant metastasis (HR 1.17, 95% CI 1.05-1.32; p = 0.006), prostate cancer specific mortality (HR 1.39, 95% CI, 1.20-1.63; p < 0.001), and overall survival (HR 1.17, 95% CI 1.06-1.29; p = 0.002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry PSA, and treatment arm. Again, looking at the RTOG/SPPORT trial,3 Dr. Parker notes that pelvic nodal therapy + prostate bed radiotherapy + short-term ADT improves time to second salvage ADT, with a possible small improvement in distant metastasis and prostate cancer survival:

 

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Dr. Parker notes that later this year we will likely have trial data coming from the RADICALS-HD trial, which is testing different durations of hormone therapy during salvage radiotherapy:

 

ASCO 2022_Chris C. Parker_Salvage Treatment_5 

To conclude his presentation, Dr. Parker discussed the timing of post-operative radiotherapy, which may be in the adjuvant setting (PSA zero), early salvage radiotherapy setting (PSA failure), or later salvage radiotherapy setting (radiologic failure). Early studies assessing the efficacy of adjuvant radiotherapy included the EORTC 22911 trial, which showed an improvement in biochemical progression free survival (HR 0.48, 98% CI 0.37-0.62) for patients receiving adjuvant radiotherapy versus RP alone. However, not surprising accordingly to Dr. Parker, with longer follow-up in this trial, there was no difference in OS between adjuvant radiotherapy vs a wait-and-see policy (HR 1.18, 95% CI 0.91-1.53).6 Additionally, in October 2020, there were three trials (RAVES,7 RADICALS-RT,8 and GETUG-AFU-179) in addition to a concomitant meta-analysis (ARTISTIC)10 that suggested non-inferiority of early salvage radiotherapy with adjuvant radiotherapy. Across the three trials, a total of 1,074 men were randomized to adjuvant radiotherapy and 1,077 to an early salvage strategy. Despite some differences in patient population and study design, the findings of the three trials were remarkably similar: there was no significant improvement in biochemical event free survival for patients receiving adjuvant radiotherapy (HR 1.12, 95% CI 0.88 to 1.42). According to Dr. Parker, this data “puts the nail in the coffin” of adjuvant radiotherapy.

 Therefore, we must decide if we are going to treat patients in the early or later salvage radiotherapy setting. Data from Tendulkar et al.1 suggest that higher pre-salvage radiotherapy PSAs lead to worse freedom from biochemical failure:

 

ASCO 2022_Chris C. Parker_Salvage Treatment_6 

 

However, based on early PSMA PET/CT data, Dr. Parker questions whether we can potentially wait to treat patients to ensure there is meaningful clinical benefit to treatment. Specifically, patients that are planned for prostate + pelvic nodal radiotherapy that have PSMA PET/CT lesions outside of the planned salvage radiotherapy treatment zone, may have major implications for salvage therapy planning for ~20% of patients in the biochemical recurrent setting.11

 

Presented by: Chris C. Parker, MD, FRCR, Royal Marsden Hospital, London, UK

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.

References:

  1. Tendulkar RD, Agrawal S, Gao T, et al. Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy. J Clin Oncol. 2016 Oct 20;34(30):3648-3654.
  2. Ghadjar P, Hayoz S, Bernhard J, et al. Dose-intensified versus conventional-dose salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial. Eur Urol. 2021 Sep;80(3):306-315.
  3. Pollack A, Karrison TG, Balogh AG, et al. The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): An international, multicentre, randomized phase 3 trial. Lancet. 2022 May 14;399(10338):1886-1901.
  4. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017;376(5):417-428.
  5. Feng FY, Huang HC, Spratt DE, et al. Validation of a 22-Gene Genomic Classifier in Patients with Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):544-552.
  6. Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: Long-term results of a randomized controlled trial (EORTC trial 22911). Lancet 2012 Dec 8;380(9858):2018-2027.
  7. Kneebone A, Fraser-Browne C, Duchesne GM, et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): A randomized, controlled, phase 3, non-inferiority trial. Lancet Oncol. 2020;21(10):1331-1340.
  8. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): A randomized, controlled phase 3 trial. Lancet 2020;396(10260):1413-1421.
  9. Sargos P, Chabaud S, Latorzeff I, et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localized prostate cancer after radical prostatectomy (GETUG-AFU 17): A randomized, phase 3 trial. Lancet Oncol 2020;21(10):1341-1352.
  10. Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localized and locally advanced prostate cancer: A prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020 Oct 31;396(10260):1422-1431.
  11. Calais J, Czernin J, Cao M, et al. 68Ga-PSMA-11 PET/CT mapping of prostate cancer biochemical recurrence after radical prostatectomy in 270 patients with a PSA level of less than 1.0 ng/mL: Impact of salvage radiotherapy planning. J Nucl Med. 2018 Feb;59(2):230-237.

 

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