Adding abiraterone acetate to standard of care prolongs survival in prostate cancer subset
Adding abiraterone acetate to androgen deprivation therapy plus docetaxel improved radiographic PFS and OS among men with metastatic castration-sensitive prostate cancer, according to data presented during the virtual ESMO Congress 2021.
Investigators on the phase 3 PEACE-1 trial added that improvements in radiographic PFS and OS were observed among the 84% of men in the control arm who received androgen signaling inhibitors.
“PEACE-1 has now clearly established that using three systemic treatments up front — ADT, docetaxel and abiraterone acetate [Zytiga, Janssen] with prednisone — is better than just two in men with de novo M1 prostate cancer,” Karim Fizazi, MD, PhD, professor of medicine and president of the Genitourinary Group (GETUG) in the department of cancer medicine at Institut of Paris Sud, told Healio.
“In our opinion,” he added, “[these] data [are] practice changing, at least for these men with high-volume disease.”
For the last 6 years, investigators knew combining ADT with either docetaxel, androgen signaling inhibitors or radiotherapy to the primary tumor for men with low metastatic burden improved OS and represented a standard of care in this population. What remained unknown, however, was whether combining those treatments on top of ADT could further improve outcomes.
Data presented by Fizazi and colleagues at this year’s virtual ASCO Annual Meeting showed adding abiraterone to ADT plus docetaxel significantly improved radiographic PFS in men with metastatic castration-sensitive prostate cancer (HR = 0.5, 95% CI, 0.4-0.62).
From the investigators’ most recent data, Fizazi highlighted that among men with high-burden metastatic prostate cancer, the triple treatment used in the PEACE-1 trial led to a marked improvement in survival, with expectations that men can live for more than 5 years as opposed to the 3 years most had expected as recently as 6 years ago.
“These men will enjoy 2.5 years of additional time without cancer progression (from a median of 2 years to 4.5 years) and also a reduction in the risk [for] death of 25%, with limited and expected additional side effects,” Fizazi said. “For men with high-volume disease (those with multiple bone metastases), this means more than 1.5 years of additional lifetime gain.”
The analysis included 1,173 men with newly diagnosed metastatic castration-sensitive prostate cancer (57% with high-volume metastases) randomly assigned to standard of care (ADT plus docetaxel), standard of care plus abiraterone, standard of care plus radiotherapy to the primary tumor, or standard of care plus abiraterone and radiotherapy to the primary tumor.
The overall type 1 error testing the abiraterone effect was 5%, researchers reported. Within the standard-of-care population, 249 events were required to detect an HR of 0.7 for OS with 80% power, they added. Investigators pooled the abiraterone groups for comparison after the drug’s effect on OS did not interact with the one of the radiotherapy groups.
Median follow-up was 4.4 years.
Results showed improved OS with abiraterone both in the overall population (median, 5.7 years vs. 4.7 years; HR = 0.83, 95% CI, 0.69-0.99) and in the standard-of-care group (median, not reached vs. 4.4 years; HR = 0.75, 95% CI, 0.59-0.96).
Additionally, Fizazi reported that among men in the standard-of-care group who developed castration-sensitive prostate cancer, 84% (n = 221of 263) went on to receive at least one life-prolonging therapy vs. 74% (n = 104 of 141) in the abiraterone group, and 81% in the control group went on to receive at least one androgen signaling inhibitor vs. 46% in the abiraterone group.
Adverse effects appeared consistent with expectations. Grade 3 to grade 5 adverse events included hypertension (22% with standard of care plus abiraterone vs. 13% with standard of care), neutropenia (10% vs. 9%), liver toxicity (6% vs. 1%) and febrile neutropenia (5% in both groups).
“Given the different mechanisms of action of docetaxel and abiraterone, and also the observation that the second agent often remains active when the first has failed in men with castration-resistant disease, we were clearly hoping for a synergistic efficacy effect when used together upfront. It is great to now see that this is, indeed, the case; not all hypotheses are confirmed by data in clinical research,” Fizazi said.
Fizazi called the results the “first step” for PEACE-1, with plans for additional analysis underway, including examining the role of radiotherapy to the primary cancer in a context of intensified systemic treatment, particularly among men with low-burden metastatic prostate cancer to accurately assess survival.
“Also, data on quality of life for the abiraterone question are pending, as well as deeper safety analysis, (for example) regarding assessment of bone loss in these men,” he added. “More generally, it is time to integrate biomarkers for decision-making in these men, and trials have already started to address this question.”
Perspective
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PEACE-1 clearly tells us, regardless of standard of care used, either ADT or ADT with docetaxel, the addition of abiraterone has a clinically meaningful OS benefit.
For those digging into all the data, an important consideration here is to remember that we’re looking at a very heterogenous group of patients in this study … and across a time lapse that’s quite long. In looking back at ASCO 2021, regarding radiographic PFS reporting, what we have today with docetaxel, again, is even more impactful here with the addition of abiraterone, regardless of standard of care used.
PEACE-1 is a practice-changing trial. The positive outcomes are meaningful when it comes to radiographic PFS and OS, with the exception of low-volume disease.
If one thing comes across (from PEACE-1 and STAMPEDE), no matter what you do tomorrow, don’t go with ADT alone with these patients. Earlier combinatorial treatment with enhanced androgen signaling inhibition is now a requirement — I don’t know what else we should be waiting for — for men with advanced hormone-sensitive prostate cancer.
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In the LATITUDE study, which identified a survival benefit for abiraterone acetate added to ADT in metastatic hormone-sensitive prostate cancer (mHSPC), it was somewhat surprising that only 55% of men achieved a deep PSA nadir of less than 0.2 ng/dL. This deep nadir was associated with longer survival, indicating that additional efforts aimed at improving remissions are needed.
The PEACE-1 study takes us a step closer by showing that abiraterone confers additional prolongation of MFS and OS even after upfront docetaxel has been administered. The relative contribution of the chemotherapy cannot be ascertained, but it can be inferred and is plausible given that clones resistant to abiraterone would not necessarily be resistant to taxane chemotherapy.
These data contrast with the ENZAMET trial results, which did not show an apparent benefit for use of enzalutamide (Xtandi; Astellas, Pfizer) after upfront docetaxel in a similar patient population. Since PEACE-1 was prospectively designed to answer the question, whereas ENZAMET was not, and the drugs being studied have distinct mechanisms of action, PEACE-1 should nevertheless be viewed as practice-changing. Importantly, however, triple therapy likely will not be appropriate for all newly diagnosed men with mHSPC. The art of medicine will require oncologists to select which men are least likely to experience unacceptable toxicity from the docetaxel based on their comorbidities and to weigh the relatively greater benefit of upfront docetaxel in high-volume patients. There may be other approaches more suitable to men with oligometastatic spread, with ongoing studies exploring the use of metastasis-directed therapy, as well as time-limited intensified ADT approaches.
As men with mHSPC live longer, it is critical to pay greater attention to survivorship. More intensive suppression of testosterone is expected to result in greater risk of osteoporosis, so oncologists will need to refine their practice related to reducing loss of bone density. Cardiovascular events over the long term also may be increased, necessitating close collaboration with primary care physicians to diagnose and effectively manage adverse changes in blood pressure, lipids and insulin resistance. Paying attention to these details will help ensure that men are best able to enjoy the longer years of cancer control they achieve with intensified mHSPC therapy.
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Perspective
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Fizazi and colleagues need to be complimented for this very well-designed study.
Their initial results showed that addition of abiraterone acetate to ADT plus docetaxel improved radiographic PFS and OS in men with metastatic castration-sensitive prostate cancer. Of note, there were no differences in incidence of side effects such as febrile neutropenia, cardiac and grade 5 complications, and other hematologic side effects between the standard-of-care and abiraterone groups, Although researchers reported higher incidences of liver toxicity (6% vs. 1%) and hypertension (22% vs 13%) in the abiraterone group.
Candidates for this trial were stratified by metastatic site, ECOG performance status (0 vs. 1-2), type of testosterone-lowering therapy and use of docetaxel. It would have been helpful if stratification of the current trial had been by ECOG performance status of 0 or 1 vs. 2. Studies have shown that patients with ECOG performance status of 2 or higher had significantly lower disease control, PFS and OS than those with performance status of 0 or 1. In addition, inclusion of BMI, tobacco consumption, diabetes treated with either oral hypoglycemic or insulin, renal insufficiency, respiratory comorbidity, cardiovascular comorbidity, neoplastic comorbidity and alcohol use disorder would have been helpful to categorize patients in each cohort.
References:
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Fizazi K, et al. Abstract LBA5_PR. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 16-21, 2021.