Expanding the use of abiraterone in prostate cancer: Is earlier always better?

Androgen deprivation therapy (ADT), the inhibition of testosterone production via orchiectomy or the administration of a luteinizing hormone-releasing hormone (LHRH) agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix), has been the mainstay of therapy in patients with newly diagnosed prostate cancer that is locally advanced or metastatic.¹ High-risk (classified as Gleason Score of ≥8) nonmetastatic prostate cancer and metastatic prostate cancer account for approximately 20% and 3% of annual new prostate cancer diagnoses respectively.² The durability of ADT as monotherapy is limited, as resistance to androgen ablation inevitably allows for uncontrolled tumor growth despite adequate castrate levels of testosterone, indicating the development of castration resistant prostate cancer (CRPC).³ Previous studies have investigated the capability of combined androgen blockade, achieved via the administration of 1^st generation androgen receptor antagonists (ARA, e.g. nilutamide, flutamide) with ADT, to delay castration resistance.⁴ These studies failed to show statistically significant clinical improvements due to the limited efficacy of such 1st generation ARAs and inadequate study design.⁴ Interest to enhance the efficacy of front-line ADT in this population was re-invigorated following FDA approval of several agents to manage patients with CRPC (e.g. docetaxel, enzalutamide, abiraterone acetate).⁵ Several studies have addressed administering these agents in combination with ADT in patients who have received limited or no prior ADT, a subtype of disease classified as castration sensitive prostate cancer (CSPC).

The use of docetaxel, a taxane antineoplastic agent, was recently investigated in combination with ADT in patients with CSPC. The GETUG-AFU 15 trial, an open label phase 3 study enrolling mostly patients with metastatic disease and <2 months of ADT (n = 385), did not demonstrate that 8 cycles of docetaxel 75 mg/m² (administered via intravenous infusion every 3 weeks) in combination with ADT improved median overall survival (OS) in comparison to ADT alone (hazard ratio [HR]: 1.01, 95% CI: 0.75 to 1.36, p = 0.955).⁶ In contrast, the CHAARTED trial, which enrolled 790 patients with metastatic CSPC (mCSPC) and administered 6 cycles of docetaxel 75 mg/m², showed a 13.6 month OS benefit (57.6 months vs. 44 months, HR for death in combination group: 0.61, 95% CI: 0.47 to 0.80, p < 0.001).⁷ The benefit of docetaxel and ADT was especially noted in patients with high volume disease (presence of ≥4 bone lesions with ≥1 beyond the vertebral bodies/pelvis or visceral metastases), with OS of 49.2 months vs. 32.2 months in patients on ADT alone (HR: 0.60, 95% CI: 0.45 to 0.81, p < 0.001).⁷ A third study, STAMPEDE Arm C (one arm of a multi-arm multi-stage randomized controlled trial), enrolled patients with newly diagnosed prostate cancer that was metastatic, node-positive, or high-risk locally advanced, or previously treated patients with high risk features.⁸ Patients were assigned to receive ADT alone (n = 1184) or in combination with six cycles of docetaxel (n = 592).⁸ An OS benefit of 10 months was observed with the addition of docetaxel to ADT in comparison to ADT alone (81 vs. 71 months, HR: 0.78, 95% CI: 0.66 to 0.93, p = 0.006).⁸ Additionally, statistically significant benefits in OS were observed in the following patient subgroups: age <70, Gleason score of 8 to 10, and metastatic disease.⁸ Potential reasons that explain the contrasting findings of the GETUG-AFU 15 study include better patient prognosis in comparison to CHAARTED and STAMPEDE, differences in subsequent therapies once patients were off study, and insufficient statistical power.⁹ Based on CHAARTED and STAMPEDE Arm C, six cycles of docetaxel in combination with ADT in patients with CSPC and high metastatic burden is considered a standard of care approach,¹⁰ despite no current FDA approved indication.

Two recent studies published in the New England Journal of Medicine have since challenged docetaxel as the sole adjunct to ADT to improve clinical outcomes in patients with mCSPC. Fizazi et al. and James et al. published results from the LATITUDE and STAMPEDE Arm G trials respectively, each addressing the use of abiraterone acetate 1000 mg orally once daily with corticosteroids (LATITUDE: prednisone 5 mg orally once daily, STAMPEDE: prednisolone 5 mg orally once daily) in combination with ADT in patients with CSPC.^11,12 Abiraterone acetate (AA) is a prodrug to the active testosterone derivative and CYP17 inhibitor, abiraterone. By decreasing intratumoral androgen production through the inhibition of CYP17, a key enzyme in the steroidogenesis pathway and the production of testosterone, abiraterone has been shown to improve clinical outcomes in patients with metastatic CRPC (mCRPC).^13,14 Combined androgen blockade with abiraterone and leuprolide was previously investigated in a neoadjuvant setting for patients with localized high-risk prostate cancer. At 12 weeks, patients who received AA with ADT had reduced PSA and serum androgen levels in comparison to patients receiving ADT alone.¹⁵ More complete androgen suppression provided rationale to study the addition of AA to ADT versus ADT alone in patients with CSPC.

The LATITUDE study was an industry-sponsored, international, multicenter, double-blind, phase 3 trial that randomly assigned 1199 patients in a 1:1 ratio to receive ADT plus AA or ADT alone.¹¹ Eligible patients were newly diagnosed (<3 months from randomization) with high-risk, mCSPC as defined by the presence of two of the following three factors: a Gleason score of 8 or more, at least 3 bone lesions, or the presence of measurable visceral metastasis.¹¹ Patients were excluded if they received prior treatment for prostate cancer, unless the patient received ≤3 months of ADT with or without concurrent 1st generation ARA therapy, one course of palliative radiation, or surgical therapy to treat symptoms associated with metastatic disease.¹¹ The study had co-primary endpoints of OS and radiographic progression-free survival (rPFS), and several secondary endpoints that included time to skeletal-related event, time to progression with respect to prostate specific antigen (PSA), time to pain progression, and time to sequential therapy.¹¹

LATITUDE demonstrated both a significant improvement in median rPFS (33.0 months vs. 14.8 months, HR: 0.47, 95% CI: 0.39 to 0.55, p < 0.001) and OS, with a relative risk of death that was 38% lower in the abiraterone and ADT group (HR: 0.62, 95% CI: 0.51 to 0.76, p < 0.001).¹¹ The study also showed statistically significant improvements in the secondary endpoints, including time to PSA progression and time to pain progression.¹¹ Increases in the number of patients with hypertension and hypokalemia in the abiraterone treatment group (15% and 16% increases respectively) were noted, attributable to concurrent mineralocorticoid administration.¹¹ Overall, LATITUDE confirmed castration naïve patients with metastatic disease (presence of bone lesions or visceral disease) or a Gleason score ≥8 could benefit from the addition of abiraterone to ADT.

Similarly, STAMPEDE Arm G randomly assigned 1917 patients with newly diagnosed metastatic, node-positive, or high-risk locally advanced (defined as two of the following: T3/T4 stage, Gleason of 8 to 10 or PSA ≥40 ng/mL) or previously treated, relapsing disease with high-risk features to ADT +/- AA in a 1:1 ratio.¹² A majority of patients were newly diagnosed and were classified with either metastatic disease (n = 941), node-positive nonmetastatic disease (n = 369), or node negative nonmetastatic disease (n = 509).¹² This study was primarily powered to detect a benefit in OS, with an intermediate primary endpoint of failure-free survival (FFS, rPFS plus biochemical recurrence determined by rising PSA) and secondary endpoints that included adverse events, symptomatic skeletal events, PFS, prostate cancer specific survival, and quality of life.¹² Abiraterone plus ADT increased the 3-year OS rate of patients by 7 percent (83% vs. 76%, HR: 0.63, 95% CI: 0.52 to 0.76, p < 0.001) and the 3-year FFS rate by 30% (75% to 45%, HR: 0.29, 95% CI: 0.25 to 0.34, p < 0.001).¹² STAMPEDE showed an increase in Grade 3–5 adverse events with the addition of abiraterone, most notably hypertension and ALT increase.¹² Stratification of the patient population demonstrated a statistically significant benefit in FFS across all demographic categories.¹² Mirroring LATITUDE, a benefit in OS was observed in patients with metastatic disease (HR: 0.61, 95% CI: 0.49 to 0.75) or Gleason score ≥8 (HR: 0.59, 95% CI: 0.48 to 0.73).¹² The subgroup analysis suggested no statistically significant OS benefit in patients with nonmetastatic disease or a Gleason score <8.¹² Additionally, the patient subgroup of age 70 years or older did not have a significant OS benefit, an observation not made on the LATITUDE study.^11,12

Taken together, these studies validated that the addition of abiraterone to ADT compared to ADT alone significantly lengthened the time to progression in patients sensitive to castration. LATITUDE and STAMPEDE Arm G confirmed an OS benefit to their respective patient populations with statistically significant and remarkably similar hazard ratios. The benefit in patients with metastatic and/or highly differentiated disease was especially noted by both studies. However, the subgroup analysis of STAMPEDE Arm G calls into question the benefit in patients with nonmetastatic disease, Gleason <8, and increased age. Despite the large number of patients included in these subgroups, additional study is still necessary to fully confirm these findings, as STAMPEDE was not originally designed to detect statistical significance in the subgroup analyses. Overall, the earlier administration of abiraterone with ADT was associated with significantly improved clinical outcomes for patients with mCSPC in comparison to ADT alone.

A follow-up statistical analysis comparing Arm C and Arm G of STAMPEDE demonstrated that despite better FFS following treatment with abiraterone and ADT in comparison to docetaxel and ADT (HR: 0.51, 95% CI: 0.39 to 0.67, p < 0.001), there was no difference between the treatments with respect to OS (HR: 1.16, 95% CI: 0.82 to 1.65, p = 0.40).¹⁶ With this evidence supporting the equal efficacy of either abiraterone or docetaxel in combination with ADT, two options for the management of patients with mCSPC now exist, each with advantages and disadvantages. Docetaxel, while administered for only six 3-week cycles, is associated with a marked increase in Grade 3–5 toxicity, most notably febrile neutropenia.⁸ Although abiraterone therapy is associated with more manageable toxicities, a significant number of patients with mCSPC will receive daily treatment for approximately 3 years before evidence of disease progression.^11,12 Additionally, the required concurrent chronic mineralocorticoid administration with abiraterone should not be considered lightly, especially in patients prone to hypothalamic-pituitary-adrenal axis suppression (e.g. elderly).¹⁷ A shorter duration of adjunct docetaxel therapy to ADT despite the risk of severe toxicity may be more optimal for some patients. Six cycles of docetaxel plus ADT upfront followed by abiraterone plus ADT until castration resistance, an approach that requires further investigation, may also provide enhanced therapeutic benefit in patients with mCSPC.¹² Ultimately, the availability of two equally efficacious treatment options should enable individual patient characteristics and preferences to dictate clinical decision making. In many instances, it is likely abiraterone plus ADT upfront may not be the best option.

While not fully understood at the current time, the implications of acquired resistance to both docetaxel and abiraterone treatment in the castration sensitive setting may also play a role in clinical decision making. It should be noted that significant genotypic and phenotypic differences between castration-sensitive and castration-resistant disease exist,^18,19 thus the resistance patterns observed in mCRPC may not be entirely applicable in mCSPC. Nonetheless, evidence of therapy-induced remittance, including possible neuroendocrine differentiation (a notable mechanism of acquired resistance that enables androgen-independent tumor cell proliferation and carries a poor prognosis), has been shown following monotherapy with docetaxel, abiraterone, and ADT.²⁰ Future characterization of patient tumors following more aggressive treatment in the castration sensitive setting is warranted to better understand patterns of resistance that are consistent with or novel to those observed in the castration resistant setting. Whether early abiraterone administration leads to a neuroendocrine phenotype is an important question that requires further investigation.

Both LATITUDE and STAMPEDE Arm G compared the second-line treatments following disease progression between the ADT alone and combination therapy arm. Patients that were given combination therapy were far more likely to receive docetaxel, whereas more patients received abiraterone or enzalutamide in the ADT alone arm. This is not surprising based on current practice to preferentially switch to chemotherapy following the failure of androgen receptor-targeted therapies in the castration resistant setting.⁵ Of particular interest, however, is the continued long term follow-up of these patients off-study. The STAMPEDE investigators noted that 1471 patients included in the second-line treatment comparison are still alive, thus the data should evolve as patients experience further disease progression and receive more therapy.¹² Perhaps an OS comparison of patients in the abiraterone plus ADT arm versus patients in the ADT alone arm who receive abiraterone monotherapy in the castration resistant setting could be made in the near future, inferring the true benefit of using abiraterone earlier in the disease course.

The discussion of how to optimally treat patients with CSPC is only just beginning, as multiple other studies are ongoing. Several studies have incorporated the use of 2^nd generation ARAs (e.g. enzalutamide, apalutamide, darolutamide) in this treatment setting. Enzalutamide provides similar clinical benefit to that of abiraterone in patients with mCRPC without the need for concurrent mineralocorticoid administration,^21,22 suggesting the possibility of alternative treatment options in patients with CSPC. Current studies investigating 2^nd generation ARAs include STAMPEDE Arm J (ADT ± abiraterone/enzalutamide; NCT00268476), TITAN (ADT ± apalutamide; NCT02489318), ARCHES (ADT ± enzalutamide; NCT02677896), and ENZAMET (ADT + enzalutamide vs. ADT + antiandrogen; NCT02446405). Other hypotheses suggest the integration of secondary hormonal manipulation with docetaxel and ADT could further improve outcomes. Two such studies include PEACE1 (NCT01957436), comparing ADT ± docetaxel versus ADT and abiraterone ± docetaxel, and ARASENS (NCT02799602), investigating ADT + docetaxel with or without darolutamide. The results of these studies will likely have an impact on the standard of care in patients with CSPC.

The results from LATITUDE and STAMPEDE Arm G will likely expand the indication of abiraterone and change the standard of care in patients with mCSPC. Clinicians now have two therapy combinations to consider in the metastatic castration sensitive setting, enabling for clinical decision making based on patient specific characteristics and preferences. Despite a more manageable toxicity profile in comparison to docetaxel, determining whether the early administration of abiraterone is better for the patient will likely rest on the commitment to long-term therapy. With the maturation of the published data and more completed studies anticipated in the next several years, the standard of care in patients with CSPC will continue to evolve, possibly allowing for multiple different therapeutic interventions to be considered. For now, abiraterone and docetaxel are equivalent and viable options to be considered in combination with ADT in patients with mCSPC.