Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer

The Unanticipated Real-World Clinical Experience

Darren M. C. Poon; Kuen Chan; S. H. Lee; T. W. Chan; Henry Sze; Eric K. C. Lee; Daisy Lam; Michelle F. T. Chan

Disclosures

BMC Urol. 2016;16(12) 

In This Article

Discussion

In the current study, we reported the efficacy and toxicity of AA in mCRPC patients from an unselected patient population in a non-trial setting. The inclusion of all AA-treated patients in all public oncology centers during a defined period serves to provide a representative picture of the efficacy of AA in clinical service setting. The clinical efficacy, notably the OS and PFS, and tolerability of AA in our post-chemo patients was similar to that of the COU-AA-301 study (Table 6), thus reproducing the efficacy of AA in the post-chemotherapy setting. However, unexpectedly, the median OS of chemo-naïve patients in our cohort (of 18.1 months) was remarkably much shorter than that reported in COU-AA-302 study (of 34.7 months). It is noted that our chemo-naïve patients with visceral disease, the patient group that was excluded in the COU-AA-302 study, had significantly inferior survival. If this small subset of poor-prognosis patients was excluded, the OS and PFS of the chemo-naïve patients without visceral metastases were still unfavorable, being similar to the whole group. Thus inclusion of patients with visceral disease in our study cannot entirely explicate the unfavorable survival outcome of chemo-naïve patients. It is also unlikely that the infrequency of post-AA treatment contributes to the unfavorable survival, as the subset of patients given post-AA treatment did not have more favorable survival than those without in the multivariate analysis. We postulate that the inferior survival outcome of our chemo naïve patients could be attributable to a relatively high tumor burden in this patient cohort, compared to that in the COU-302 study. This is supported by a higher baseline PSA level (median: 212 ug/l) in our patients as compared to that in the COU-AA-302 study (median: 42 ug/l). Besides, the inclusion of chemo-naïve patients with poor prognostic features in our study could also account for the unsatisfactory survival results. For example, our patient cohort included symptomatic patients (only asymptomatic or mildly symptomatic patients were included in COU-AA-302 study) and patients with ECOG 2 (patients with ECOG 2 or above were excluded in COU-AA-302 study), and a higher proportion of elderly patients: 63.8 % of patients were age above 75 in our cohort, compared to 34 % in COU-AA-302 study.

It is worth noting that despite the somewhat disappointing survival outcome in chemo-naïve patients treated with AA; nearly 60 % of symptomatic patients had pain alleviation. In fact, such a rate of pain control is similar to that in post-chemo patients, and was also comparable to that in the COU-AA-301 study, despite the pain assessment tools were not identical between ours and the pivotal studies (Table 6). To our knowledge, the present study is the first one to report on efficacy of pain control for symptomatic chemo-naïve patients with AA.

While data on efficacy of AA on chemo-naive patients with visceral metastases or symptomatic disease is being awaited, the present study suggests that patients with high tumor burden, visceral metastases and symptomatic disease may have inferior outcome with AA. An exploratory analysis of the visceral disease subgroup in the COU-AA-301 study[6] has demonstrated that the presence of visceral disease is prognostic but not predictive of the response to AA.[12] Nonetheless, there are growing evidences that the efficacies of therapies are different in chemo-naïve patients and post-chemo patients.[13] In contrast, the presence of symptomatic or visceral metastasis did not confer inferior clinical outcome to docetaxel-based chemotherapy, as reflected by the subgroup analysis in the TAX 327 study.[14] With the lack of randomized trial specifically addressing AA efficacy in chemo-naïve patients with visceral or symptomatic disease, the practice of advocating AA in this particular subgroup should be further scrutinized in the context of clinical trial. Indeed, the data in the present study may support a treatment paradigm of offering AA to mCRPC patients with relatively low tumor burden, and chemotherapy for patients with high tumor burden, and visceral disease. Besides, based on the present study's data, patients with symptomatic disease may also be considered for AA to help pain control, though the survival outcome is less than favorable.

The achievement of PSA response after AA as a favorable prognosticator is in consistency with prior experience based on the data from COU-AA-302 and 301 studies, in which substantial correlation between survival and PSA kinetics was established.[15] Conversely, the absence of PSA response could potentially be used as a biomarker to select patients earlier for alternative or additional treatment in future clinical trial.

In our study, more than half of patients with initial PSA flare had ultimate PSA response to AA and, furthermore, there was no substantial difference in clinical outcome in patients with or without PSA flare. Consequently, in view of the not uncommon occurrence of PSA flare in some patients, PSA response is better determined at least 12 weeks after treatment, as recommended by the PCWG-2 and the premature discontinuation of AA when encountering initial PSA flare is not suggested.[11] In contrast, the practice of further continuation of AA beyond progression is not advised as the meta-analysis in our study has exemplified that there was no additional enhancement of survival with extended AA.

Short duration of response to prior ADT (<10 months) was associated with an unfavorable survival in chemo-naïve patients with AA in this study. Our finding substantiates the other reports that the short response to ADT was associated with poorer efficacy with AR-pathway targeted therapy, in particular AA, in mCRPC patients.[16,17] And this echoed the statement made in the latest European consensus that short duration of response to ADT could be used to identify patients with increased risk of primary resistance to AR-pathway targeted agents.[18]

Limitations existed in the present study, which include the typical shortcomings of retrospective study such as under-reporting of adverse events, incompleteness of data collection and selection bias etc. However, we consider these limitations would not affect the ability to capture the survival outcome of AA in this study. And the inadequate sample size, difference in follow-up protocols and the policy of post-AA treatment among different hospitals were the other weakness of the current study. Of note, unlike prospective study, regular imaging was not mandatory in our study and this could deprive some patients from other life-prolonging treatment earlier before any clinical or biochemical progression existed. Finally, the follow-up time for the chemo-naive group is comparatively inadequate and the inferior outcome in this group may not be the ultimate result. Our group will plan for another follow-up study in the future.

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