Abiraterone has become the first-choice treatment for men with metastatic prostate cancer.
In the modern era of cytotoxic chemotherapy for common solid tumors, advanced prostate cancer came late to the table. The principal reason for this was the already established role of androgen deprivation therapy (ADT), with its near 100% chance of success and its contrastingly acceptable toxicity profile, coupled with a philosophy of using “the most active and least toxic treatment first.” Although a role for chemotherapy was eventually established in the treatment of men with advanced prostate cancer in whom ADT was failing, it seemed counterintuitive to use it in men who retained sensitivity to the relatively benign intervention of ADT. Initially establishing a niche among men in whom both ADT and docetaxel had failed, the new hormonal therapies abiraterone acetate and enzalutamide rapidly became a first-choice treatment for men with metastatic castration-resistant prostate cancer (CRPC), with most patients and physicians preferring to defer chemotherapy until abiraterone or enzalutamide had failed.[2-5] This shift occurred in the absence of any head-to-head trials comparing abiraterone or enzalutamide with docetaxel, and despite the substantially lower acquisition cost of docetaxel. In other words, patients and physicians made instinctive decisions as to which drug was more suited to their needs during the predominantly asymptomatic or minimally symptomatic stage of the disease after initial failure of ADT.
Despite this, it is still clear that, for most men with metastatic CRPC, there is benefit to be had from sequential use of docetaxel and abiraterone or enzalutamide. Until recently, for most men the preferred treatment pathway was ADT, followed by the addition of abiraterone or enzalutamide, and then docetaxel when this approach failed.
Two large trials inform our understanding of the use of abiraterone (in combination with low-dose prednisone) predominantly in patients with newly diagnosed advanced prostate cancer. Both trials completed accrual before docetaxel became standard treatment in this setting, and so both trials excluded men who had received prior docetaxel.
LATITUDE was a multicenter, double-blind, randomized, phase III trial conducted in 34 countries that compared abiraterone plus prednisone (5 mg once daily) with dual placebos in men with high-risk metastatic prostate cancer at the time of diagnosis. “High-risk” disease was defined in this trial as two or more of the following three features: Gleason score ≥ 8, ≥ 3 bone metastases, and/or visceral disease. The coprimary endpoints were overall survival and radiographic progression–free survival (rPFS).
STAMPEDE is a multi-arm, multi-stage trial in men starting long-term ADT. As such, the trial has included multiple interventions in a group of men, which includes not only men presenting with metastatic disease, but also men with high-risk locally advanced and recurrent prostate cancer. The abiraterone comparison of STAMPEDE (arm G vs arm A) was an open-label trial comparing abiraterone plus prednisolone (5 mg once daily) with ADT alone. The primary endpoint was overall survival, and failure-free survival (FFS; defined, predominantly, as prostate-specific antigen [PSA] progression) was a key secondary endpoint in the final analysis. For the purposes of this debate, I will focus on the subgroup of the 52% of patients who had metastatic disease at presentation.
Both trials have yielded striking and similar results, with 38% and 39% reductions in the risk of death in LATITUDE and STAMPEDE, respectively, in men with metastatic disease. Neither trial has achieved sufficient follow-up to enable an estimate of the median survival gain, but informal extrapolation of the survival curves leads to an estimated median survival gain in excess of 20 months. The true magnitude of the survival gain in LATITUDE may be compromised by crossover after unblinding for those men who were still progression-free and receiving placebo.
There was a very significant delay in rPFS in men receiving abiraterone in LATITUDE, with a 53% reduction in risk and a median improvement in rPFS of 18.2 months. Routine scanning was not performed in STAMPEDE, and so rPFS was not calculated. However, the risk of failure of any sort was reduced by 69% in those with metastatic disease who received abiraterone. In both trials, the tolerability of abiraterone was similar to what was seen in the metastatic CRPC setting, despite the lower dose of corticosteroids.
Due to its unique design features, there was a brief period when patients entering the STAMPEDE trial were directly randomized between docetaxel and abiraterone. Although this was not a formally powered comparison, it offers the only head-to-head data in this setting. There was no difference in overall survival between the two treatments (hazard ratio [HR], 1.16; 95% CI, 0.82–1.65, in favor of docetaxel), although abiraterone was associated with a superior FFS (HR, 0.51; 95% CI, 0.39–0.67). At 1 and 2 years, there was no difference in toxicity. This analysis included patients with high-risk locally advanced disease.
Despite these recent advances, for most patients, metastatic prostate cancer remains a fatal condition. Patients’ expectations of treatment differ from one patient to another, and so it is unlikely that a unified treatment pathway will be right for all men. While survival is important, many will trade survival time for quality of life, and most strive for treatment that prolongs the high-quality phase of their survival. However, the months between diagnosis and first progression will, for most, be among the highest-quality months of the remainder of their lives. This precious progression-free period is a time when most patients are enjoying a fully active and productive life. Therefore, a major objective of treatment intensification in metastatic hormone-sensitive prostate cancer (HSPC) is the prolongation of progression-free survival.
The data demonstrate that treatment with abiraterone achieves the objectives of prolonging both overall and progression-free survival to an extent rarely seen in solid tumor trials. The common methodology used throughout the STAMPEDE trial permits high-quality indirect comparison. Docetaxel reduced the risk of FFS by 39%, compared with 69% for abiraterone. Even in the undersized direct comparison, there was a significantly greater effect on FFS with abiraterone compared with docetaxel. This seemingly greater effect of abiraterone may be explained by its direct effect on PSA transcription, resulting in a spurious exaggeration of the effect when compared with the less direct effects of docetaxel on PSA production. However, even with the more conservative measure of rPFS used in the LATITUDE trial, the magnitude of the benefit is greater than the effect on PSA-driven endpoints seen in the docetaxel comparisons of STAMPEDE, GETUG-AFU 15, and CHAARTED.[9-11] Indirect comparison of the effects on overall survival suggest that the 38% to 39% risk reduction observed with abiraterone is greater than the 23% reduction seen in the meta-analysis of the docetaxel trials.
There is no debate that, during treatment, docetaxel will be associated with a greater burden of toxicity and a higher risk of severe toxicity or death compared with abiraterone. This analysis is simplistic, since it fails to take into account the very different durations of therapy. Time from first to last dose of docetaxel is 15 weeks, compared with the median duration of abiraterone, which, in the trials, was 24 to 33.2 months. However, mature experiences of prolonged use of abiraterone in the metastatic CRPC setting confirm that the toxicity profile is compatible with a stable and high quality of life, adding little to underlying ADT.
Real-life experience suggests that as many as 62% of men presenting with metastatic HSPC are not suitable for treatment with docetaxel. Reasons include excessive comorbidity, reduced performance status, and patient choice. It is undoubtedly the case that many, if not most, of these men will be suitable for, and may wish to receive, abiraterone. Indeed, the higher proportion of elderly and lower-performance-status men enrolled in the abiraterone trials compared with the docetaxel trials would support the position that abiraterone remains effective even in men who are less suitable for treatment with docetaxel.
The high cost of abiraterone when compared with the low acquisition cost of docetaxel is a clear factor against its use in 2018. However, even at this cost, given the sizable effect on overall survival and, more importantly, the likely gain in quality-adjusted life-years (due to the high proportion of time gained in the pre-progression state), abiraterone is likely to demonstrate good value in high-income healthcare systems, at least when compared with ADT alone. As patent expiries loom for abiraterone around the world, it will inevitably be the case that the price will drop very substantially in coming years, meaning that abiraterone may well become more cost-effective than docetaxel, despite the prolonged duration of therapy.
Despite their differences, the trials of abiraterone and docetaxel have irreversibly changed the way we view and treat metastatic prostate cancer, clearly demonstrating that early intervention results in significantly superior outcomes. We can anticipate very rapid evolution in this field: trials including sequential use of docetaxel and abiraterone or other androgen receptor–targeted therapies, as well as the combination of enzalutamide and abiraterone, have already completed accrual in this setting, and emerging agents in metastatic CRPC will, in all likelihood, rapidly transition to the early phase of the disease. As we move into the era of precision medicine and genomics, it will inevitably make sense to use such approaches at the time of initial diagnosis. In the meantime, many patients have a choice of treatments available to them, a choice that will be guided by their own expectations of treatment, as well as the differing profiles of the drugs.
Financial Disclosure:Dr. Jones has received advisory board and speaker honoraria from Janssen, as well as speaker honoraria and research funding from Sanofi Genzyme.
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