The first paper discussed by Dr. Borno was by Eastham et al. “Cancer and Leukemia Group B 90203 (Alliance): Radical Prostatectomy with or without Neoadjuvant Chemohormonal Therapy in Localized, High-Risk Prostate Cancer” published in the Journal of Clinical Oncology.1 This trial tested the hypothesis that chemohormonal therapy with ADT plus docetaxel before radical prostatectomy would improve biochemical progression-free survival over radical prostatectomy alone. Men were eligible for this trial if they had cT1-T3a disease, serum PSA <100 ng/mL, negative bone scan, and no radiographic evidence of metastatic disease. The primary endpoint for this trial was 3-year biochemical progression-free survival with biochemical failure defined as a PSA level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Overall, 788 men were randomly assigned and median follow-up time was 6.1 years. Dr. Eastham and colleagues found no difference in 3-year biochemical progression-free survival between neoadjuvant chemohormonal therapy plus radical prostatectomy and radical prostatectomy alone (0.89 versus 0.84, respectively; 95% CI for the difference, -0.01 to 0.11; p = 0.11):
However, neoadjuvant chemohormonal therapy was associated with improved overall biochemical progression-free survival (HR 0.69, 95% CI 0.48 to 0.99), improved MFS (HR 0.70, 95% CI 0.51 to 0.95), and improved OS (HR 0.61, 95% CI 0.40 to 0.94) compared with radical prostatectomy alone.
The key conclusions of this trial as highlighted by Dr. Borno are as follows:
- There was no difference in 3- or 5-year biochemical progression-free survival or prostate cancer-specific survival between the treatment groups
- Improvement in event free survival was observed in men treated with neoadjuvant chemohormonal therapy and radical prostatectomy
- The combination of neoadjuvant docetaxel with ADT before radical prostatectomy should not be considered a treatment option for men with localized, high-risk prostate cancer at this time
The second paper discussed by Dr. Borno was by Sternberg et al. “Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer” published in The New England Journal of Medicine and highlighting an overall survival benefit.2 The PROSPER trial was a double-blind, phase 3 trial, among 1,401 men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. With a data cut off of October 15, 2019, median follow-up in the PROSPER trial was approximately 48 months. There was a total of 466 deaths, of which 288 occurred among those randomized to enzalutamide and 178 among those randomized to placebo. Prostate cancer related deaths were more common than non-prostate cancer related deaths in this cohort, both among patients randomized to enzalutamide (178 and 110 deaths, respectively) and those randomized to placebo (136 and 42 deaths, respectively). Median overall survival was 67.0 months (95% CI 64.0 to not reached) among patients receiving enzalutamide and 56.3 months (95% CI 54.4 to 63.0) among patients receiving placebo, corresponding to a 27% relative reduction in the risk of death for patients receiving enzalutamide (HR 0.73, 95% CI 0.61 to 0.89; p = 0.001):
The authors utilized O’Brien–Fleming-type alpha-spending function on the basis of three planned analyses. As a result of adjustment for multiplicity of testing, the p-value threshold for significance was 0.021. Thus, the analysis of overall survival met the threshold for statistical significance. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.
Key conclusions for this study were that (i) enzalutamide treatment in men with nmCRPC and a rapidly rising PSA level resulted in a significantly longer overall survival than placebo, and (ii) the adverse event profile was similar to the established safety profile of enzalutamide.
The third paper discussed by Dr. Borno was by Smith et al. “Apalutamide and overall survival in prostate cancer” published in European Urology.3 Similar to the aforementioned PROSPER trial, the SPARTAN trial evaluated apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer and PSA doubling time of ≤10 months. SPARTAN included 1,207 patients that were randomized 2:1 to apalutamide (240mg/d) or placebo, plus on-going ADT. After MFS was met and the study was unblinded, 76 (19%) patients still receiving placebo crossed over to apalutamide. At the time of data cut-off, there were 428 deaths (of a required 427 events), of which 274 occurred among those randomized to apalutamide and 154 among those randomized to placebo. Median overall survival was significantly longer among men receiving apalutamide (73.9 months, 95% CI 61.2 to not reached) than placebo (59.9 months, 95% CI 52.8 to not reached), corresponding to a relative reduction of 21.6% in the risk of death (HR 0.784, 95% CI 0.64 to 0.96, p-value 0.0161; O’Brien–Fleming threshold of 0.046 for statistical significance). The authors conducted further analyses, accounting for those patients randomized to placebo who crossed over to apalutamide therapy without disease progression:
Furthermore, the observed beneficial effect of apalutamide in SPARTAN was consistent across subgroups based on patient age, race, region, performance status, PSA, PSA doubling time, use of a bone-sparing agent, and presence of locoregional disease.
Dr. Borno provided the following concluding remarks for the overall survival data on SPARTAN:
- The final analysis demonstrated improved metastasis free survival, time to symptomatic progression, and overall survival
- Apalutamide lengthens the time before initiation of cytotoxic chemotherapy
- The safety profile of apalutamide was consistent with that which has been previously reported
The final paper discussed by Dr. Borno was the Phase II TRITON2 study by Abida et al. “Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration” published in The Journal of Clinical Oncology.4 TRITON2 assessed patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily. Key efficacy endpoints were objective response rate (per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease) and locally assessed PSA response (≥ 50% decrease from baseline) rate. Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. The confirmed objective response rate per independent radiology review was 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and by investigator assessment was 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients). The median radiographic progression free survival was 9.0 months (95% CI 8.3-13.5):
Additionally, the confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). Objective response rates were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration.
Key conclusions from TRITON2 as provided by Dr. Borno are as follows:
- A large proportion of patients achieved a confirmed radiographic response with rucaparib treatment in both blinded and central independent radiology review, and investigator-assessed analyses
- There was evidence of radiographic and PSA response across subgroups based on baseline patient characteristics and genomic characteristics
- Men with mCRPC and a BRCA alteration who receive a PARP inhibitor in this setting achieve higher objective and PSA response rates than those observed with prior treatments in an unselected population
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021
References:
- Eastham JA, Heller G, Halabi S, et al. Cancer and Leukemia Group B 90203 (Alliance): Radical Prostatectomy with or without Neoadjuvant Chemohormonal Therapy in Localized, High-Risk Prostate Cancer. J Clin Oncol. 2020 Sep 10;38(26):3042-3050.
- Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2197-2206.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021 Jan;79(1):150-158.
- Abida W, Patnaik A, Campbell D, et al. Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol 2020 Nov 10;38(32):3763-3772.