Abiraterone acetate plus prednisolone ‘new standard of care’ in prostate cancer subset
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Two years of abiraterone acetate plus prednisolone-based therapy significantly improved survival among men with high-risk nonmetastatic prostate cancer starting androgen deprivation therapy, according to results of the STAMPEDE trial.
The addition of the androgen receptor antagonist enzalutamide increased toxicity but did not have a noticeable impact on efficacy of the combination, which researchers recommended as the new standard of care for this patient population.
Results of the multi-arm, multi-stage platform trial were presented during the virtual ESMO Congress 2021.
“[Through the STAMPEDE trial], we had combined [men with metastatic and nonmetastatic prostate cancer] and the data from analysis in 2017 for the [men with nonmetastatic disease, for whom] there was no certainty and too few events, in the control arm and the ADT arm and the patients treated with ADT and abiraterone,” Gerhardt Attard, MD, PhD, John Black Charitable Foundation endowed chair in urological cancer research at University College London, said during a presentation. “The question we sought to address with this analysis is whether there was a benefit for abiraterone acetate [Zytiga, Janssen] in high-risk, nonmetastatic prostate cancer.”
The latest results, Attard said, should result in the treatment being considered “the new standard of care.”
The STAMPEDE trial included men with high-risk node-positive or high-risk node-negative disease with any two of these features: stage T3/T4, PSA 40 ng/mL, Gleason score of 8-10, as well as men with relapsing disease with high-risk features. As part of two separate comparisons, researchers randomly assigned the men to ADT vs. ADT with 1,000 mg abiraterone acetate plus 5 mg oral daily prednisolone (AAP), or ADT vs. ADT with AAP plus 160 mg once-daily enzalutamide (Xtandi; Astellas, Pfizer) for 2 years unless local radiotherapy was omitted when treatment could be to progression, Attard and colleagues wrote.
The current analysis included 1,974 patients in the U.K. and Switzerland randomly assigned 1:1 to ADT with or without AAP (n = 914) or to ADT with or without AAP plus enzalutamide (n = 1,060). The two groups were well-balanced, with a median age of 68 years (range, 43-86), median PSA of 34 ng/mL (range, 0.4-2,773) and Gleason score of 8 to10 (79%); 39% were node positive and 85% planned for local radiotherapy. The subgroup of patients assigned to ADT with or without AAP was partially reported in 2017, thus, a one-sided type 1 error rate was set to 1.25%, Attard and colleagues noted.
Metastasis-free survival (MFS), defined as time to death or distant metastases, served as the primary endpoint.
Results showed that 180 MFS events occurred in the study-treatment group and 306 in the control group. At 6 years, AAP-based therapy improved MFS (HR = 0.53, 95% CI, 0.44-0.64) and OS (HR = 0.6; 95% CI, 0.48-0.73).
“Based on these results, all men with high-risk nonmetastatic prostate cancer should be considered for 2 years of abiraterone,” Attard said in a press release. “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.”
The AAP treatment translated to improvement in 6-year rates of MFS (69% to 82%), OS (77% to 86%) and prostate cancer-specific survival (85% to 93%) when compared with standard treatment alone.
“The magnitude of benefit here is much greater than was previously estimated,” Attard said.
Additionally, the treatment effect was consistent in major subgroups and between AAP (HR for MFS = 0.54; 95% CI, 0.43-0.68) and AAP-plus-enzalutamide (HR for MFS = 0.53; 95% CI, 0.39-0.71) randomization periods, researchers noted (HR for interaction = 1.02; 95% CI, 0.7-1.5).
“We saw no clinically relevant evidence of treatment effect heterogeneity,” Attard said.
Attard added that more information is needed to determine the optimal length of AAP therapy.
“We have not reported long-term complication beyond 2 years because we are unsure about the reliability of adverse event reporting after patients have completed treatment,” he said. “We have no data on treatment durations other than 2 years. Shorter (treatments) may be as good; longer may be more effective. Relapsed patients are underrepresented.
“However,” he added, “we’ve consistently seen the size of treatment benefits in metastatic patients and (now) we’re reporting this in the nonmetastatic population, so I would expect that the patients in the middle would derive the same benefit.”
Perspective
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Adriana Pedraza, MD
Prostate cancer is the most common malignancy in men in the United States and the second leading cause of cancer death, with approximately 34,000 estimated deaths by 2021.
Men with high-risk M0 and those with N1 prostate cancer have worse oncologic outcomes. Therefore, efforts have been made to implement multimodal treatments in this scenario.
Neoadjuvant, concurrent and adjuvant-intense hormone interventions combining ADT and abiraterone acetate-based therapy showed encouraging outcomes in this analysis of the STAMPEDE trial, improving metastasis-free survival, as well as survival after 2 years of therapy. However, it is not yet clear whether early initiation of these drugs will determine subsequent resistance to agents targeting the androgen receptor. In addition, a personalized approach taking into account androgen receptor splice variants such as AR-V7 may refine selection of patients who are ideal candidates for this combination.
Given the required long-term exposure to the regimen described, adverse effects and quality of life must be carefully evaluated. Finally, the rapidly advancing field of immunotherapy may expose broader options for multimodal treatment in these cases, likely leading to fewer adverse effects.
A coordinated multidisciplinary approach is essential to guide the treatment and follow-up of these patients, incorporating precision medicine into their care.
Perspective
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Tanya Dorff, MD
Treating men with metastatic prostate cancer more aggressively from the start by adding abiraterone or enzalutamide to standard ADT has substantially improved survival. The new report from the STAMPEDE multi-arm trial showed that intensified therapy also benefits men with high-risk, nonmetastatic prostate cancer. This builds upon decades of work by the NRG (formerly RTOG) and EORTC cooperative groups, which defined that 2 to 3 years of adjuvant ADT improved outcomes for men receiving definitive radiation for high-risk prostate cancer, as well as the SWOG 9921 study that suggested adjuvant ADT reduced recurrence after prostatectomy for men with high-risk disease features. Although the latter often is reserved for node-positive patients, it is notable that both SWOG 9921 and STAMPEDE considered men with other high-risk features to be eligible. Specifically, STAMPEDE enrolled men whose disease met two of three high-risk features (Gleason 8-10, PSA >40, or T3/T4 stage) even without lymph node involvement.
These new data also confirm the lack of advantage for combining abiraterone plus enzalutamide, which we have seen from other studies, both in later-stage castration-resistant disease and earlier in the neoadjuvant setting. There appears to be a maximum amount of benefit we can derive from targeting the androgen receptor pathway — at least with existing agents. The next advances, therefore, will need to come from combination therapies that target potential resistance pathways (such as Pi3K/AKT), that eliminate aggressive clones with cytotoxic (or perhaps poly(ADP-ribose) polymerase, or PARP, inhibitor) therapy, or that engage the immune system with checkpoint inhibitors.
Abiraterone does not add much toxicity for patients, but it can be costly. Ensuring access for all men with advanced prostate cancer will pose challenges to health care systems in terms of ensuring equity and bearing the added expense. One evolving frontier that may mitigate this problem to some degree is the work being done to apply molecular categorization to treatment decision-making in high-risk, nonmetastatic prostate cancer. For instance, the Decipher test is currently being used to prospectively assign patients with better prognosis to standard therapy or to de-intensified therapy in the ongoing NRG-GU009 trial PREDICT-RT (NCT04513717). These types of integral biomarker studies will be critical for evolving beyond our current “one-size-fits-all” treatment approach to eventually facilitate more judicious application of adjuvant therapy and intensified adjuvant therapy.
Perspective
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Eleni Efstathiou, MD, PhD
Androgen signaling inhibition is a prevailing therapeutic strategy in advanced prostate cancer, [with] reproducible outcomes in a total of 14 phase 3 studies, none with negative results. This has suggested throughout, including with these data, that early use is better for advanced disease, but also that more may end up being less.
There are still a lot of unmet needs. What do we do about more effective therapeutic strategies for localized, high-risk disease?
The STAMPEDE trial group is one with an impressive track record in practice-changing contributions. We have a study design that’s as close to everyday practice as you can have.
Are the STAMPEDE trial’s latest results truly practice changing? Yes.
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