(UroToday.com) 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. Following earlier presentations by Dr. Alberto Bossi (PEACE-1 radiotherapy results), Dr. Andrew Armstrong (ArteraAI long-term ADT predictive biomarker), and Dr. Praful Ravi (prognostic value of 6-months PSA level post-radiotherapy from ICECaP), Dr. Karen Hoffman delivered the discussant session for these studies.
Beginning with the PEACE-1 radiotherapy data presented by Dr. Bossi, Dr. Hoffman noted that current evidence for the use of pelvic radiotherapy in the low-volume mHSPC disease space comes from the HORRAD and STAMPEDE Arm H trials. HORRAD was a multicenter trial of 432 patients with previously untreated, de novo mHSPC men randomized in a 1:1 fashion to either ADT with external beam radiotherapy or ADT alone. Subgroup analysis by number of metastatic lesions suggested a potential (albeit not statistically significant) OS benefit for radiotherapy in patients with <5 metastatic sites (HR: 0.68, 95% CI: 0.42 to 1.10).1 STAMPEDE (Arm H) was an open label, randomized controlled phase III trial of 2,061 men with de novo mHSPC randomized to standard of care + radiotherapy or standard of care. An OS benefit was observed in the low volume group (HR: 0.68, 95% CI: 0.52 to 0.90) with restricted mean survival time improved by 3.6 months from 45.4 to 49.1.2 Updated results after a median follow up of 61.3 months demonstrated that prostate radiotherapy continued to demonstrate OS benefits in patients with low metastatic burden (HR: 0.64, 95% CI: 0.52 to 0.79), with no benefit seen in patients with high metastatic burden (HR: 1.11, 95% CI: 0.96 to 1.28; interaction p=0.001).3
Dr. Hoffman argued that the benefit of local therapy on survival depends on the effectiveness of systemic therapy. While this remains an empiric concept, the rationale here is that there may be a “sweet spot” for radiotherapy in mHSPC patients. This concept is depicted in the figure below. Based on the patient disease characteristics and systemic treatment received, it is likely that HORRAD and STAMPEDE fall within that “sweet spot” of where the benefit of local therapy on survival is optimal. Conversely, trials evaluating radiotherapy in a more advanced setting (i.e., along the downward slope of this curve) may prove to be less effective. 
From a practical standpoint, patients in the HORRAD/STAMPEDE trials were more treatment-naïve compared to those in PEACE-1. As demonstrated below, all patients in HORRAD and 82% of patients in STAMPEDE had only received ADT as systemic therapy. Conversely, 50% of low-volume patients in PEACE-1 had received docetaxel and half were randomized to receive abiraterone.4
As such, patients in the PEACE-1 trial constitute a more heavily pre-treated cohort of patients that may be along the “downward slope” of the curve above, and this may explain why prostate radiotherapy failed to demonstrate an OS benefit in the low-volume cohort in this trial. 
Furthermore, we see that the magnitude of rPFS benefit for adding prostate radiation to standard of care (SOC) + abiraterone was similar to the benefit of adding abiraterone to SOC systemic therapy. This again highlights the important role that treatment intensification plays in this setting and explains, at least in part, the negative OS results seen in the PEACE-1 trial in the low-volume patients. 
So why was no benefit observed in the SOC only arm when radiotherapy was added? In other words, why do the results differ from STAMPEDE Arm H? Dr. Hoffman offered the following reasons:
- More effective initial SOC therapy (50% received docetaxel in PEACE-1 compared to 18% in STAMPEDE)
- More effective next-line systemic therapies
- Differences in patient populations?
- The median OS in the STAMPEDE SOC arm was 64 months, compared to 83 months in the PEACE-1 SOC arm
Interestingly, patients in the PEACE-1 trial receiving prostate radiotherapy had improvements in time to serious GU events, irrespective of systemic therapy used (SOC +/- abiraterone). This is in distinction to the results observed in STAMPEDE, where there were no differences in symptomatic local events. Possible reasons for this include use of a higher radiation dose in PEACE-1 (74 vs 67 Gy) and more effective systemic therapy impacting local cell kill.
The PEACE-1 trial similarly demonstrated that prostate radiotherapy improved castration resistance-free survival. It is postulated that a benefit of prostate radiotherapy is destruction of subclones resistant to systemic therapy or that will become resistant to systemic therapy.
Dr. Hoffman concluded the PEACE-1 discussant segment by highlighting what we still need to learn about prostate-directed therapy:
- Does surgery provide the same benefit as radiation?
- Ongoing studies in this space include SWOG S1802 and IP2-ATLANTA
- Does metastasis-directed therapy impact the benefit of prostate-directed therapy?
- How do we select patients most likely to benefit from prostate-directed radiation?
These were Dr. Hoffman’s suggestions for what we should do differently in light of PEACE-1:
- Continue to administer prostate radiation to patients with de novo, limited metastases and castrate-sensitive disease
- Counsel our patients differently in the context of more effective systemic therapy that prostate radiation:
- Prevents local symptoms
- Improves cancer control
- Prevents castration resistance development
- Unclear whether there is an OS advantage
- Can consider prostate radiation for select patients with higher volume metastasis to prevent GU symptoms
Next, Dr. Hoffman discussed the abstract presented by Dr. Armstrong evaluating the ArteraAI long-term ADT predictive biomarker. She also highlighted the paucity of predictive biomarkers in this space. She noted we often try to use prognostic classifiers for predictive purposes.
In contrast to these prognostic tests, such as Decipher®, the ArteraAI long-term AD biomarker was designed for predictive purposes. The validation analysis in the NRG/RTOG 9202 cohort demonstrated that the ArteraAI biomarker was a significant predictor of the utility of long-term ADT use in this cohort (interaction p=0.04). As demonstrated below, patients in the biomarker negative group (n=407) derived no benefit from long-term ADT use, compared to short-term ADT use (HR: 1.06, 95% CI: 0.61 – 1.84, p=0.84). Conversely, patients in the biomarker positive group had significant improvements in the distant metastasis rates with long-term ADT (HR: 0.55, 95% CI: 0.41 – 0.73, p<0.001). Accordingly, approximately 1/3 of men with high-risk prostate cancer could have safely avoided long-term ADT based on the results of this predictive biomarker analysis. 
Dr. Hoffman argued that further validation studies for this biomarker are not needed, given that this biomarker has already been validated in the “high-quality”, large, multicenter, phase III trial NRG/RTOG 9202. As such, this biomarker already meets a higher standard than when Prolaris®, Oncotype®, Decipher® were initially endorsed by the NCCN. This biomarker meets standards for use in clinical practice. However, there are opportunities for confirmation in other clinical trials comparing short- and long-term ADT, with digital pathology not consuming any tissue.
Dr. Hoffman argued that the most noteworthy aspect of this study is that use of this biomarker has the potential to reduce the number of NCCN high/very-high risk patients receiving long-term ADT, with 29% of such patients potentially having had the ability to be spared long-term ADT had this biomarker been utilized. While Dr. Armstrong and colleagues suggested that 43% of intermediate-risk patients would have benefited from long-term ADT had this biomarker been used, Dr. Hoffman argued that we need to know the absolute benefit of long-term ADT for intermediate-risk patients before considering lengthening treatment. 
Dr. Hoffman made sure to emphasize that the ArteraAI long-term ADT predictive biomarker should not be used in isolation, and we should consider patient preferences and disease/patients characteristics when considering ADT treatment duration.
Next, Dr. Hoffman discussed the abstract presented by Dr. Ravi evaluating the prognostic value of PSA nadir ≥0.1 ng/ml within 6 months of completion of radiotherapy +/- ADT. The ICECaP group has previously established metastasis-free survival (MFS) as a surrogate endpoint for OS, accelerating trials for localized prostate cancer.5
This has important implications for trial design in this setting, as it still takes 10 to 12 years to complete trials for intermediate and high-risk prostate cancer.
In this study utilizing individual patient data from ICECaP, Dr. Ravi and colleagues demonstrated that PSA nadir ≥0.1 ng/ml within 6 months of radiotherapy completion was strongly associated with subsequent MFS, cancer-specific survival, and OS. PSA nadir provides a signal of what is happening at a much earlier timepoint. While this is not the first study to demonstrate this association, it is the largest to do so. However, Dr. Hoffman highlighted that this study does not establish surrogacy for PSA nadir ≥0.1 ng/ml, and, as such, PSA nadir cannot be used as a trial endpoint for the time being. She argued however that PSA nadir can be used a criteria to select patients for escalation or de-escalation trials, and PSA nadir can serve as an early signal to determine whether to continue a trial intervention. One of the limitations of this study is that only 2% of patients in the radiotherapy alone arm achieved a PSA nadir <0.1 ng/ml, and as such the results of this analysis are not as applicable to this patient group.
Presented by: Karen E. Hoffman, MD, MHSc, MPH, Associate Professor, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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:
- Boeve LMS, Hulshof MCCM, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410-418.
- Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
- Parker CC, James ND, Brawley CD, et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Medicine. 2022;19(6):e1003998.
- Fizazi K, Foulon S, Carles J, Roubaud G, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): A multicentre, open-label, randomized, phase 3 study with a 2 x 2 factorial design. Lancet. 2022;399(10336):1695-1707.
- Xie W, Regan MM, Buyse M, et al. Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol. 2017;35(27):3097-3104.