The combination of docetaxel plus prednisone has been a standard therapy in advanced prostate cancer since 2004.1 Since then, there have been multiple randomized phase III trials comparing this standard of care with additional drug therapy. None has demonstrated improvement in outcome.
Lenalidomide (Revlimid) is an oral derivative of thalidomide (Thalomid), which is widely used in the treatment of myeloma. Its precise mechanism of action is uncertain, but it has immunomodulatory and antiangiogenic properties.
Early trials of thalidomide and lenalidomide in patients with prostate cancer showed some evidence of clinical activity, although the combination of lenalidomide with docetaxel had not been explored beyond a phase I trial with a small, nonrandomized cohort expansion prior to the initiation of the phase III MAINSAIL trial. Preclinical data, however, had shown enhanced cytotoxicity of docetaxel by lenalidomide in models of prostate cancer.
MAINSAIL Details
The MAINSAIL trial,2 recently reported by Petrylak and colleagues and reviewed in this issue of The ASCO Post, was a large, randomized, double-blind, placebo-controlled trial of docetaxel plus prednisone with or without lenalidomide. It failed to demonstrate any benefit from adding lenalidomide to docetaxel plus prednisone in men with metastatic castration-resistant prostate cancer. In fact, patients receiving lenalidomide had a significantly worse outcome for both survival (the primary endpoint of this trial) and progression-free survival than did those receiving placebo in the control arm of the trial.
The causes for this apparent detrimental effect of lenalidomide are not clear. Although excess toxicity was seen in the lenalidomide arm, there were few excess deaths during treatment, suggesting that fatal immediate toxicities were not likely to be the cause. This does not rule out the possibility that there were latent toxicities causing excess mortality in those patients who had received lenalidomide, although there is no particular rationale as to why that might have been the case.
Prostate-specific antigen response rates were similar in both arms of the trial, suggesting that lenalidomide was not reducing the efficacy of docetaxel by, for example, a drug interaction. However, the total amount of docetaxel received did differ between the arms—those patients receiving lenalidomide received a median of six cycles, compared to eight in the control arm.
Furthermore, there were more dose reductions of all drugs for toxicity in the lenalidomide arm than in the control arm. Therefore, one plausible contributor to the reduced efficacy among patients receiving lenalidomide may have been reduced exposure to docetaxel experienced by those patients.
Lessons Learned
Several thousand men with metastatic castration-resistant prostate cancer have now been enrolled in randomized phase III trials of docetaxel with or without an additional agent. This comes at great cost. The first cost, as seen here, is that trial participation may sometimes result in harm to some patients. Some of the men who received lenalidomide in the MAINSAIL trial are likely to have been better off had they not participated. This is, of course, an acceptable risk in ethically conducted trials such as MAINSAIL, but we owe it to our patients to take all reasonable steps to minimize such harm.
Second, by participating in these trials, several thousand patients, and countless other finite resources employed in clinical trials, were unavailable for other research, thus, perhaps, delaying the discovery of more impactful treatments. Finally, the financial costs, though largely borne by the pharmaceutical industry in most of these trials, are enormous. It is therefore vital that we learn lessons from these experiences, which will enable us to conduct future clinical trials with greater efficiency while minimizing the number of patients who are exposed to ineffective or even detrimental treatments.
There was preclinical evidence of synergy between lenalidomide and docetaxel, but the results of the MAINSAIL trial demonstrated that these data did not in fact predict meaningful clinical synergy. Better preclinical models could assist in testing therapeutic hypotheses prior to clinical development in the future.
Although the MAINSAIL trial was terminated early by the independent data monitoring committee, thereby taking steps to minimize harm to trial participants, alternative development pathways could be considered that may result in more efficient early stopping of trials of ineffective or harmful treatments. Phase II trials may be used to identify ineffective treatments at an early stage but are limited by the absence of robust intermediate endpoints for survival in prostate cancer and the need to randomize when exploring combination strategies. Furthermore, the need to conclude a phase II trial before initiating a phase III evaluation will result in slower implementation of a truly effective treatment, thus potentially delaying therapeutic progress.
Still a Need for Docetaxel Combinations?
During a decade in which five new systemic therapies have been licensed as monotherapy agents for the treatment of metastatic castration-resistant prostate cancer, it is easy to question the need to develop new drugs in combination with docetaxel. However, at the time this trial was conceived, docetaxel was the only treatment that had been proven to prolong survival in this disease.
Trials of new treatments given earlier in the course of the disease (eg, in the “prechemotherapy” niche) demand long follow-up for which there is no acceptable surrogate endpoint for overall survival, and interventions among those with chemorefractory disease may be impacted by the relative poor health of the participants. Furthermore, placebo-controlled trials may prove unpalatable in a setting in which standard therapy is being delayed (as may be perceived to be the case in the prechemotherapy niche). Thus, it is easy to see how a combination with the standard of care was an obvious developmental pathway at the time the MAINSAIL trial was designed.
Recent advances in systemic therapy have changed the positioning of docetaxel in routine practice and have confirmed the value of sequential rather than concurrent combination therapies as an effective way of managing this disease. However, what evidence we have would suggest that these new therapies have not negated the role for docetaxel, which remains a useful, life-prolonging therapy for many men with metastatic castration-resistant prostate cancer at some point in the disease pathway.
Moreover, recent data from the E3805 CHAARTED trial have suggested that the addition of docetaxel at the point of initial androgen deprivation may dramatically improve outcomes in men with metastatic prostate cancer.3 This may reawaken interest in combining docetaxel with other agents in the hope that the substantial survival gains seen may be further enhanced. ■
Disclosure: Dr. Jones reported no potential conflicts of interest.
References
1. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.
2. Petrylak DP, Vogelzang NJ, Budnik N, et al: Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 16:417-425, 2015.
3. Sweeney C, Chen YH, Carducci MA, et al: Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. J Clin Oncol 32(5s suppl):Abstract LBA2, 2014.
Dr. Jones is Senior Lecturer and Honorary Consultant in Medical Oncology at the University of Glasgow College of Medicine and the Institute of Cancer Sciences, Glasgow, Scotland, United Kingdom.
