The first paper discussed by Dr. Hall was by Shore et al. “Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer” published in The New England Journal of Medicine.1 HERO was a 48-week, global, Phase III trial that randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 ratio to receive relugolix 120 mg orally QD after a single one (n=624) or leuprolide acetate 3-month depot injection (n=310). The primary endpoint was to achieve and maintain serum testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at day 4, profound castration (< 20 ng/dL) rates at days 4 and 15, prostate-specific antigen (PSA) response rate at day 15, and follicle-stimulating hormone (FSH) levels at week 25. Testosterone recovery was evaluated in a subset of 184 patients. Key inclusion criteria included confirmed advanced prostate cancer (biochemical or clinical relapse, metastatic disease, or advanced localized disease), requiring ≥1 year of androgen deprivation therapy (ADT), serum testosterone ≥150 ng/dL, serum PSA >2.0 ng/mL, and ECOG score of 0-1. The patient demographics were well balanced between the two groups, with 71% of men ≤75 years of age, >2/3 of men were Caucasian, and ~40% of men were from European countries. The median PSA for those on relugolix was 11.7 ng/mL (range 0.02-5517), compared to 9.4 ng/mL (range 0.20-2874) for those receiving leuprolide. Total cardiovascular risk factors included 91.6% of those receiving relugolix compared to 94.2% for those receiving leuprolide. A total of 96.7% (95% confidence interval [CI] 94.9%-97.9%) of men on relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. The difference of 7.9% (95% CI 4.1%-11.8%) demonstrated non-inferiority (margin -10%) and superiority (p < 0.0001) of relugolix to leuprolide.
All key secondary efficacy endpoints tested demonstrated the superiority of relugolix over leuprolide (p < 0.0001), including:
- The proportion of patients with PSA response at day 15 followed with confirmation at day 29: 79.4% for relugolix vs. 19.8% for leuprolide
- Cumulative probability of testosterone suppression to <50 ng/dL on day 15: 98.71% for relugolix vs. 12.05% for leuprolide
- Cumulative probability of profound testosterone suppression to <20 ng/dL on day 15: 78.38% for relugolix vs. 0.98% for leuprolide
- Cumulative probability of testosterone suppression to <50 ng/dL on day 4: 56.04% for relugolix vs. 0% for leuprolide
- Mean FSH level at the end of Week 24: 1.72 IU/L for relugolix vs. 5.95 IU/L for leuprolide
In the testosterone recovery subset, median T levels were 270.76 ng/dL in the relugolix compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy.
In a prespecified analysis, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (2.9% vs. 6.2%, respectively), otherwise, the safety and tolerability profiles were generally similar. Among a subset of patients with a history of MACE, a MACE event occurred in 3.6% of patients on relugolix compared to 17.8% of patients on leuprolide. Taken together, patients receiving relugolix had a 54% reduction in risk of MACE. The most common adverse event reported for >10% of patients in any treatment group was hot flush (54.3% for relugolix vs. 51.6% for leuprolide).
Dr. Hall concluded that in the HERO trial, the oral GnRH antagonist relugolix showed sustained testosterone suppression superior to that of leuprolide. Additionally, there was a 54% lower risk of major adverse cardiovascular events than with leuprolide, however, the numbers were very small (2.9% vs. 6.4%). Finally, testosterone suppression with relugolix was both non-inferior and superior to that of leuprolide.
So, what is the standard of care? Dr. Hall notes that there are several points in favor of relugolix as a new standard of care include:
- In patients with a history of pre-existing cardiovascular disease, the cardiovascular events/deaths seem reduced with a GnRH antagonist
- Adherence is reported as very high with this oral medication
- The side effect profile appears favorable, even when including radiotherapy
- There are a favorable testosterone response and rebound
Points against relugolix as a new standard of care are as follows:
- Adherence is not certain in this broad population
- Oncologic efficacy remains untested, is rapid testosterone response a good thing?
- “Definitive therapeutic” success when combined with radiotherapy remains untested
- Drug-drug interactions are unknown
The second paper discussed by Dr. Hall was by Phillips et al. “Outcomes of Observation vs. Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial” published in JAMA Oncology.2 Stereotactic ablative body radiotherapy is an exciting new application of external beam radiation therapy that involves the delivery of very high (“ablative”) doses of radiation usually between 1-5 fractions. Applying stereotactic ablative body radiotherapy to oligometastatic disease or oligorecurrent disease is an appealing novel strategy that could delay changes (or initiation) of systemic therapy. The vast majority of stereotactic ablative body radiotherapy is exceedingly well-tolerated and data is continuing to emerge rapidly in this disease space. The Phase II ORIOLE trial randomized 54 men in a 2:1 ratio to receive stereotactic body radiotherapy or observation. The primary endpoint for this trial was progression at 6 months, defined as a PSA increase, radiographic or symptomatic progression, ADT initiation, or death. Progression at 6 months occurred in 7 of 36 patients (19%) receiving stereotactic body radiotherapy and 11 of 18 patients (61%) undergoing observation (p = 0.005). Furthermore, treatment with stereotactic body radiotherapy improved median progression-free survival (not reached vs. 5.8 months; hazard ratio [HR] 0.30, 95% CI 0.11-0.81; p = 0.002):
For those patients in the stereotactic body radiotherapy arm that had a PSMA PET-CT scan, the proportion of men with disease progression at 6 months was 5% in those who did not have any untreated lesions, compared to 38% in those who did have some untreated PSMA avid lesions (p=0.03).
Dr. Hall made the following concluding remarks regarding the ORIOLE trial:
- Treatment with stereotactic body radiotherapy for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by prostate-specific membrane antigen (PSMA)-targeted PET
- Stereotactic body radiotherapy induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit of stereotactic body radiotherapy
- These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates
The final paper discussed by Dr. Hall was by Spratt et al. “Prostate Radiotherapy with Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis” published in The Journal of Clinical Oncology.3 Controversy exists regarding the optimal sequencing strategy for ADT, and whether neoadjuvant ADT or adjuvant ADT is better remains poorly understood. A common clinical practice, prior to the publication by Spratt et al., was the use of neoadjuvant ADT for two months prior to the initiation of radiation therapy. For this systematic review and individual patient meta-analysis, two randomized Phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's RTOG 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. RTOG 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary endpoint of this meta-analysis was progression-free survival. Over a median follow-up of 14.9 years, 1,065 patients were included (531 neoadjuvant and 534 adjuvant) in the analysis. Progression-free survival was significantly improved in the adjuvant group (15-year progression-free survival, 29% vs. 36%; HR 1.25, 95% CI 1.07 to 1.47):
Biochemical failure (sub-distribution hazard ratio [sHR] 1.37, 95% CI 1.12 to 1.68), distant metastasis (sHR 1.40, 95% CI 1.00 to 1.95), and metastasis-free survival (HR 1.17, 95% CI 1.00 to 1.37) were all significantly improved in the adjuvant group.
Dr. Hall noted the following conclusions from this individual patient meta-analysis:
- These findings support concurrent and adjuvant ADT when administered with prostate-directed radiotherapy rather than neoadjuvant
- While many looked at two months of neoadjuvant ADT as a “mandatory” interval before starting radiotherapy, these results certainly question that historic standard
Presented by: William A. Hall, Md, Associate Professor, Department of Radiation Oncology and Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
Written By: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
References:
1. Shore, Neal D., Fred Saad, Michael S. Cookson, Daniel J. George, Daniel R. Saltzstein, Ronald Tutrone, Hideyuki Akaza et al. "Oral relugolix for androgen-deprivation therapy in advanced prostate cancer." New England Journal of Medicine 382, no. 23 (2020): 2187-2196.
2. Phillips, Ryan, William Yue Shi, Matthew Deek, Noura Radwan, Su Jin Lim, Emmanuel S. Antonarakis, Steven P. Rowe et al. "Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial." JAMA oncology 6, no. 5 (2020): 650-659.
3. Spratt, Daniel E., Shawn Malone, Soumyajit Roy, Scott Grimes, Libni Eapen, Scott C. Morgan, Julia Malone et al. "Prostate radiotherapy with adjuvant androgen deprivation therapy (ADT) improves metastasis-free survival compared to neoadjuvant ADT: an individual patient meta-analysis." J Clin Oncol (2020): JCO2002438-JCO2002438.