APCCC 2024: Debate: How to Best Manage a Fit Patient with High-Risk Localised and Locally Advanced Prostate Cancer? How to Select Patients for Adjuvant Therapy After Radical Prostatectomy and How to Treat Them?

(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) held in Lugano, Switzerland between April 25^th and 27^th was host to a high-risk and locally advanced prostate cancer session. Dr. Jason Efstathiou discussed how to best select fit patients with high-risk localized or locally advanced prostate cancer for adjuvant therapy following radical prostatectomy and how to treat them.

Dr. Efstathiou began with a case presentation of a 55-year-old man with pT3bN+ Gleason 4+5 disease with a pre-operative PSA of 14 ng/ml and a 7% chances of remaining disease-free at 5 years post-operatively, per the MSKCC nomogram. Should this patient receive adjuvant radiotherapy? 

For patients with adverse feature(s) and no lymph node metastases, the current NCCN guidelines recommend monitoring (category 1, preferred) with consideration of early radiotherapy for detectable and rising PSA or PSA >0.1 ng/ml. Adjuvant external beam radiotherapy +/- ADT may also be considered for these patients. Conversely, among those with lymph node metastases, monitoring with early salvage treatment for detectable and rising PSA or PSA >0.1 ng/ml and immediate ADT +/- radiotherapy are both reasonable options.

Dr. Efstathiou noted that there has been an increase in the use of radical prostatectomy for patients with high-risk disease, which has concurrently led to an increase in post-operative radiotherapy indications and usage.¹ He noted that adjuvant radiotherapy (i.e., when there is no evidence of residual disease – undetectable PSA) should be considered when there is a significant risk of future recurrence/microscopic residual disease in the surgical bed/pelvis based on pathology to improve local control and prevent dissemination/metastasis.
What defines an undetectable PSA? This has important implications for the selection of post-operative use of radiotherapy. Undetectable PSA is defined as <0.1 ng/ml in most contemporary studies. NCCN defines a detectable PSA as a PSA that increases on two or more determinations or that increases to PSA >0.1 ng/ml. Conversely, the 2024 AUA/ASTRO/SUO salvage radiotherapy guidelines define biochemical recurrence post-prostatectomy as a rise in PSA ≥0.2 ng/ml with a confirmatory value >0.2 ng/ml. There is a lack of prospective data evaluating ultra-sensitive PSA. If using ultrasensitive PSA, the Panel recommends verifying a rising trend (either two consecutive rises with PSA ≥ 0.1 ng/mL or three consecutive rises at any PSA level) as was done in RADICALS-RT. RADICALS defined biochemical relapse as two consecutive rises with a PSA ≥0.1 ng/ml or three consecutive rises. As such, we see there is significant variation in defining detectable PSA. However, the ‘optimal’ PSA cut-off varies by the clinicopathologic risk of recurrence, and Dr. Efstathioiu noted that the ‘bar’ may be as low as a single PSA level ≥0.05 ng/ml in high-risk patients.

There is evidence to support the use of adjuvant radiotherapy in high-risk patients. EORTC 22911, SWOG 8794, and ARO 9602 all showed a biochemical progression-free survival benefit for adjuvant radiotherapy, compared to observation, for patients with adverse pathologic features.^2-4 However, the use of adjuvant radiotherapy in clinical practice remains low (estimated <10% of patients who meet the criteria).⁵

An updated report of the RADICALS-RT trial of adjuvant versus early salvage radiotherapy was recently published in the Annals of Oncology. At a median follow-up of 7.8 years, there were no significant differences in freedom from distant metastases (93% versus 90%) and overall survival (HR: 0.98, p=0.92). However, patients receiving adjuvant radiotherapy had worse urinary and fecal incontinence one year after randomization (p=0.001), with fecal incontinence remaining significant after ten years (p=0.017).⁶
If patients opt for early salvage therapy, there is clear evidence that initiating salvage radiotherapy at lower PSA levels is associated with superior biochemical survival outcomes.⁷
What about adjuvant radiotherapy in patients with pN+ disease? Retrospective studies suggest a benefit to adding radiotherapy to ADT in pN+ patients.

Can genomic classifiers/risk scores inform post-radical prostatectomy practice? These tests are recommended to be used when they have the potential to change management and should not be ordered reflexively per guidelines (NCCN, AUA, ASCO). The NCCN guidelines note that: “If a radical prostatectomy exhibits adverse pathologic features (pT3a, node-positive) and the PSA is undetectable, the Decipher Genomic Classifier may help risk stratify men and identify those who are most likely to benefit from postoperative adjuvant versus early salvage radiotherapy. These retrospective studies currently lack prospective validation and long-term follow-up.” In 2015, Den et al. demonstrated in a cohort of 188 patients with pT3 or margin-positive prostate cancer who underwent postoperative radiotherapy that among patients with a Decipher® score <0.4, there was no benefit to adjuvant radiotherapy, compared to salvage radiotherapy. Conversely, among patients with a Decipher score ≥0.4, there was a metastasis-free survival benefit for adjuvant radiotherapy.⁸
The Decipher® score can also be combined with other clinicopathologic risk factors to risk stratify those patients that are most likely to benefit from adjuvant radiotherapy. Dalela et al. demonstrated in 2017 that patients with ≥2 of the following risk factors (pT3b-4, Gleason Score 8-10, lymph node invasion, and Decipher® score >0.6) were more likely to benefit from adjuvant radiotherapy.⁹

Should patients undergoing adjuvant radiotherapy receive concurrent ADT? The DADSPORT (Duration of Androgen Suppression with Post-Operative Radiotherapy) meta-analysis pooled data from four trials evaluating androgen deprivation therapy use with postoperative radiotherapy. This meta-analysis included results from RG/RTOG 9601, GETUG-AFU 16, NRG/RTOG 0534, and RADICALS-HD. This analysis included a total of 4,452 men with a median follow-up of ≥8 years. There was no clear improvement in overall survival with hormone therapy compared to no hormone therapy (HR: 0.87, 95% CI: 0.75 – 1.01), irrespective of duration of androgen suppression:      
What about duration of ADT use with adjuvant/salvage radiotherapy? Results of the RADICALS-HD trial were presented at ESMO 2022. This arm of the RADICALS platform is a randomized comparison assessing the concurrent use and duration of androgen suppression in patients with an indication for post-operative radiotherapy who had not received prior post-operative ADT. Following radical prostatectomy but prior to the initiation of their radiotherapy, patients were randomized to either no ADT (“None”), 6 months ADT (“Short”) or 24 months ADT (“Long”).
    
Over a median follow-up of 9 years, in the None versus Short comparison, based on 268 metastasis-free survival events, 6 months of androgen suppression did not improve metastasis-free survival compared to no androgen deprivation (HR: 0.89; CI: 0.69 - 1.14; 79% vs 80% event-free at 10 years). Similarly, overall survival was not improved (HR: 0.88; 95% CI: 0.65 - 1.19) nor was freedom-from-distant-metastasis (HR: 0.82; CI: 0.58 - 1.15). However, the time to salvage ADT was delayed (HR: 0.54; 95% CI: 0.42 - 0.70):    In the comparison of Short versus Long duration of androgen deprivation therapy, based on 313 metastasis-free survival events, 24 months of ADT improved metastasis-free survival (HR: 0.77; 95% CI: 0.61 - 0.97; 72% vs 78% at 10 years), freedom-from-distant-metastases (HR: 0.63; 95% CI: 0.47 - 0.85), and delayed the time to salvage ADT (HR: 0.73; 95% CI: 0.59 - 0.91). No significant improvements in overall survival were noted (HR: 0.88, 95% CI: 0.66 – 1.17):

Notably, results of the None versus Long comparison did not demonstrate a metastasis-free survival benefit (HR: 0.94, 95% CI: 0.53 – 1.68). Use of androgen suppression was not associated with a significant increase in toxicity as measured using RTOG grades.

What about further hormone treatment intensification with addition of an androgen receptor pathway inhibitor to ADT? The NRG GU008 trial is evaluating the addition of apalutamide to radiotherapy + ADT in patients with node-positive prostate cancer and detectable PSA following radical prostatectomy.
Can genomic classifiers/ risk scores inform ADT use with salvage radiotherapy? Using data from the NRG/RTOG 9601 trial of salvage radiotherapy +/- 2 years of high-dose bicalutamide in patients with positive margins or pT3 disease and pre-salvage radiotherapy PSA of 0.2–4 ng/ml, Feng et al. demonstrated that a higher Decipher® score was associated with worse rates of distant metastases, prostate cancer-specific and overall survivals on multivariable analyses.¹⁰
Dr. Efstathiou concluded as follows:

• Early salvage radiotherapy is favored over adjuvant radiotherapy in most patients
• Consider adjuvant radiotherapy in otherwise fit, motivated, very high-risk patients with ≥2 of the following risk factors:
  • pT3b-4
  • Gleason score 8-10
  • pN+
  • Decipher score >0.6
• In high-risk patients, use lower thresholds to initiate ‘ultra-early salvage or adjuvant-plus’ radiotherapy
• If giving adjuvant radiotherapy, it implies high-risk disease. Thus, Dr. Efstathiou would recommend treating the prostate bed and pelvic lymph nodes, in addition to short-term versus long-term ADT, depending on risk factors
  • May consider genomic classifiers or artificial intelligence tools to help with informed decision-making
• The goal is to avoid (or delay) radiotherapy in those who we can, without missing a window to cure patients who are guaranteed to recur

Presented by: Jason Efstathiou, MD, DPhil, Professor of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, 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 2024 Advanced Prostate Cancer Consensus Conference, Lugano, Switzerland, April 25^th - April 27^th, 2024

References:

1. Mahal B, Butler S, Franco I, et al. Use of Active Surveillance or Watchful Waiting for Low-Risk Prostate Cancer and Management Trends Across Risk Groups in the United States, 2010-2015. JAMA. 2019;321(7): 704-6.
2. Thompson Jr IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. 20026;296(19): 2329-35.
3. Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380(9858): 2018-27.
4. Wiegel T, Bartkowiak D, Bottke D, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014;66(2): 243-50.
5. Rakic N, Sood A, Dalela D, et al. A Nationwide Persistent Underutilization of Adjuvant Radiotherapy in North American Prostate Cancer Patients. Clin Genitourin Cancer. 2020;18(6): 489-99.
6. Parker CC, Petersen PM, Cook AD, et al. Timing of Radiotherapy (RT) After Radical Prostatectomy (RP): Long-term outcomes in the RADICALS-RT trial [NCT00541047]. Ann Oncol. 2024; S0923-7534(24)00105-4.
7. Tendulkar RD, Agarwal S, Gao T, et al. Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy. J Clin Oncol. 2016;34(30): 3648-54.
8. Den RB, Yousefi K, Trabulsi EJ, et al. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol. 2015;33(8): 944-51.
9. Dalela D, Santiago-Jimenez M, Yousefi K, et al. Genomic Classifier Augments the Role of Pathological Features in Identifying Optimal Candidates for Adjuvant Radiation Therapy in Patients With Prostate Cancer: Development and Internal Validation of a Multivariable Prognostic Model. J Clin Oncol. 2017;35(18): 1982-90.
10. Feng FY, Huang H, 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;7(4): 544-52.