GU cancer

Survival benefits with androgen receptor signalling inhibitors seen in prostate cancer

Treatment intensification with currently available androgen receptor signalling inhibitors improves survival in men with hormone/castration-sensitive prostate cancer (CSPC), according to results presented at the ESMO Congress 2021.

The PEACE-1 study showed that addition of abiraterone acetate plus prednisone (AAP) produced clear survival improvements in patients with metastatic prostate cancer, the conference heard.

A second trial, the STAMPEDE study, showed that in men with non-metastatic but high-risk prostate cancer, two years of the AAP combination significantly improved metastasis-free survival and survival.

The study investigator for the PEACE-1 trial explained that androgen deprivation therapy (ADT) has long been the standard of care for decades for men with metastatic prostate cancer, and in 2015, docetaxel was shown to improve survival when added to ADT.

More recently, abiraterone, a next generation hormonal agent, has also shown to improve survival when added to ADT but until now it has not been known whether one or both agents should be added to ADT to achieve the best outcomes.

The PEACE-1 phase III trial therefore investigated adding abiraterone acetate–prednisone (AAP) to standard of care (ADT with or without docetaxel) in 1173 patients with de novo metastatic CSPC.

The results showed that median overall survival (OS) was improved with the addition of AAP (5.7 years versus 4.7 years; hazard ratio [HR] 0.82;) and improved by 25% in patients receiving ADT plus docetaxel (not reached versus 4.4 years; HR 0.75).

Among patients who developed castration-resistant disease in the ADT plus docetaxel standard-of-care control arm, 84% then received at least one life-prolonging therapy and 81% received next-generation hormonal therapy, compared with 74% and 46%, respectively, of patients in the ADT plus docetaxel plus AAP arm.

Toxicity was as expected, with no apparent synergistic adverse events from the combination.

Study investigator Professor Karim Fizazi from the University of Paris-Saclay said PEACE-1 had established that triplet treatment should be offered to men with CSPC, especially those with multiple metastases.

For men with high-burden metastatic prostate cancer, the triplet treatment used in PEACE-1 provided 2.5 additional years without cancer progression and approximately 18 additional months of life, he noted.

“For the first time these men can expect to live more than five years whereas before 2015 their median survival was less than three years. By 2022 all three treatments will be generic drugs which should improve access for patients worldwide,” he said.

At an ESMO symposium to discuss the results, Dr Maria De Santis from Charité Universitätsmedizin, Berlin, said the results would change the standard of care.

“In patients with metastatic CSPC, we already knew that early treatment intensification improved survival significantly, but the question was if doublets or triplet therapy should be used. This has now been answered in the PEACE-1 study,” she said.

Non-metastatic CSPC

Encouraging results were also presented in the non-metastatic CSPC setting from the STAMPEDE trial. This study involving 1974 patients in the UK & Switzerland found that at six years, men who had received standard treatment plus AAP for two years had an improvement in metastasis-free survival from 69% to 82%, an improvement in overall survival from 77% to 86% and an improvement in prostate cancer specific survival from 85% to 93% – compared to standard treatment alone.

Adding enzalutamide to AAP increased toxicity, but this was described by the researchers as having no discernible effect on efficacy.

“Based on these results, all men with high-risk non-metastatic prostate cancer should be considered for two years of abiraterone,” said study author Professor Gerhardt Attard of University College London.

“This will involve more hospital visits during this period to manage administration of the drug but by reducing subsequent relapse, may reduce the overall burden for both patients and health services.”

Professor Attard added that more information was needed on the optimal length of AAP therapy, and it was possible that giving AAP for a shorter time may be equivalent and longer may be even more effective.

Dr De Santis said oncologists have been eagerly awaiting OS data for non-metastatic prostate cancer patients with high-risk, locally advanced disease – the so-called M0 CSPC setting.

“Until now it was unclear if the major failure-free survival improvements would translate into an OS benefit. This is a completely new patient (sub)group that has not been included in other published trials. With the clinically relevant improvements in survival seen in STAMPEDE, I expect this kind of treatment intensification to be implemented as a standard of care,” she said.

“The addition of systemic treatment with AAP for at least two years in this population will change our former treatment strategy which has been only ADT plus or minus radiotherapy to the prostate for many years.”

Dr De Santis said the findings could potentially be implemented in daily practice immediately as there was no need to wait for the approval of a new drug, and generic AAP was currently much cheaper than other androgen receptor signalling inhibitors.


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