Abiraterone should feature in the new standard of care for nonmetastatic prostate cancer, in addition to having recently been hailed as such for metastatic castration-resistant prostate cancer. Both calls were made by experts in presentations at the European Society for Medical Oncology (ESMO) Annual Meeting 2021.
The latest claim is for the combination of abiraterone acetate (Zytiga) and androgen deprivation therapy (ADT) for the treatment of men with high-risk, nonmetastatic prostate cancer.
It is based on the most recent results from the multi-arm, multistage STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial.
Those results show that for men with high-risk cancer that had not yet metastasized, 2 years of therapy with abiraterone and ADT resulted in a 47% reduction in the risk for metastasis and a 40% reduction in the risk for death compared with ADT alone.
Adding enzalutamide (Xtandi) to the abiraterone/ADT combination increased toxicity but did not improve efficacy.
“We show that 2 years of abiraterone-based therapy significantly improves metastasis-free survival and overall survival of high-risk nonmetastatic prostate cancer [patients] starting androgen deprivation therapy and should be now considered a new standard of care,” commented lead investigator Gerhardt Attard, MD, PhD, from University College London, London, United Kingdom.
At the meeting, this presentation followed presentation of results from the PEACE-1 trial, which showed that the addition of abiraterone to standard of care produced a “clinically meaningful improvement in survival” for men with de novo metastatic castration-sensitive prostate cancer, as reported by Medscape Medical News.
Sat for 15 Years on the Shelf
Attard noted that abiraterone, which was developed three decades ago, “had a bumpy ride initially; it spent 15 years on the shelf.” But in the ensuing years, “tens of thousands of men’s lives have been improved by the work of the chemists and biologists that developed this drug.”
Abiraterone is indeed an oldie but goodie, said Eleni Efstathiou, MD, PhD, from Houston Methodist Cancer Center, Houston, Texas, who was the invited discussant.
“Our progress report, from actually a clinical research and scientific perspective, is that androgen signaling inhibition is the prevailing therapeutic strategy in advanced prostate cancer with over and over and over reproducible outcomes and a total of 14 phase 3 studies, none negative,” she said.
The evidence also suggests that earlier use of androgen signaling inhibitors is better, she added.
Regarding STAMPEDE, she commented that “this is an investigator group with an impressive track record in practice-changing contributions. We have a study design as close to everyday practice as you can have it and a full transparency on the website” regarding protocol amendments and adaptations.
“The main thing is that regardless of the wonderful data and the detail of the data that we saw, these are practices that are accessible to the community, and the therapeutic index is clearly in favor,” she said.
Comparison Trial
Attard reported results from two comparisons ― abiraterone with ADT vs ADT alone (arm A, n = 921), and ezalutamided plus abiraterone added to ADT vs ADT alone (arm B, n = 1060). The median duration of therapy was approximately 2 years.
The participants were men with M0 node-positive disease or high-risk node-negative disease, defined as meeting at least two of the following four criteria: stage III or IV disease; prostate-specific antigen (PSA) level of ≥40 ng/mL; Gleason score of 8–10; relapsing disease.
The groups were well balanced with respect to age (median, 68 years), PSA level (median, 34 ng/mL), node positivity (39%), and Gleason scores of 8–10 (79%). Only 3% of patients were receiving therapy after experiencing relapse with a prior line of treatment.
Local radiotherapy was planned for 99% of patients newly diagnosed with node-negative disease, 71% newly diagnosed with N1 disease, and 7% of previously treated patients.
Superior MFS and OS
After a median follow-up of 72 months (85 months for arm A, 60 months for arm B), the primary endpoint of 6-year metastasis-free survival rate was 69% among patients treated with ADT alone, compared with 82% among those treated with ADT plus abiraterone with or without enzalutamide. This translated into a hazard ratio (HR) for metastasis or death with abiraterone of 0.53 (P < .00001).
The HRs were virtually identical in the ADT plus abiraterone-only group (0.54) and the group that received enzalutamide as the third drug (0.54; P for both > .00001).
The benefits of abiraterone with or without enzalutamide were seen across all subgroups except patients with worse World Health Organization performance status (1 or 2 vs 0). Abiraterone benefited patients regardless of nodal status, age older than or younger than 70 at randomization, regular use of nonsteroidal inflammatory drugs or aspirin, or planned radiotherapy.
The 6-year overall survival rate was 77% with ADT alone, vs 86% with abiraterone (HR, 0.60; P < .00001).
“The magnitude of benefit here was much greater than previously estimated,” Attard said.
There were no significant differences in treatment effect with the addition of enzalutamide, he added.
Secondary outcomes, which included prostate cancer–specific survival and progression-free survival, were also significantly better with combined therapy than with ADT alone.
“Unnecessary Safety Compromise”
Adverse events that occurred during therapy included grade 3 erectile dysfunction, hypertension, fatigue, and grade 3 or 4 transaminitis with the addition of enzalutamide. There were three deaths in the abiraterone-alone group (one event each of rectal adenocarcinoma, pulmonary hemorrhage, and a respiratory disorder), and four in the abiraterone plus enzalutamide group (two events each of septic shock and sudden death).
“Enzalutamide plus abiraterone and ADT obviously poses an unnecessary safety compromise for the bulk of our patients, and regardless of that, even when you’re just using a drug like abiraterone, which we feel all very comfortable with, detailed monitoring remains of paramount importance,” Efstathiou commented.
Attard acknowledged that the study was limited by the lack of reporting on complications beyond 2 years. Other limitations were that there were no data on treatment duration other than 2 years, patients who had experienced relapse were underrepresented, and there was a lack of evidence for the efficacy of single-agent androgen-receptor antagonists.
Efstathious also noted that the study did not include quality-of-life data, and he pointed out that radical prostastectomy was not available as a primary treatment option.
The STAMPEDE trial is supported by the UK Medical Research Council, Cancer Research UK, Janssen, and Astellas Pharma. Attard has received consulting fees, speaking fees, and grant support from Janssen, Astellas, and others. Efstathiou has received research support or consultant/advisory fees from Janssen-Cilag, Sanofi, and others.
European Society for Medical Oncology (ESMO) Annual Meeting 2021: Abstract LBA4_PR. Presented September 19, 2021.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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