Metastatic hormone-sensitive prostate cancer (mHSPC) is a type of prostate cancer in which tumor spreads beyond the prostate into the body and has not been treated with androgen receptor therapy (ADT). The treatment landscape of mHSPC is changing rapidly. Although ADT is the backbone of treatment in mHSPC, the appearance of docetaxel and abiraterone acetate have led to a prolonged OS time in patients and have become the SOC for mHSPC [18]. However, since 2019, NGARIs, such as enzalutamide, apalutamide, and darolutamide, have been included as a potential therapeutic approach for mHSPC. With an increasing number of available treatment options for mHSPC, selecting an optimal treatment option has become increasingly difficult, especially regarding NGARIs. Hence, we conducted a systematic review and NMA to estimate the efficacy of NGARIs in patients with mHSPC.
First, we included three NGARIs evaluated in four trials that demonstrated an OS benefit in patients with mHSPC [5–8]. As mentioned previously, docetaxel has become the SOC in patients with mHSPC. Hence, patients in the four trials included in this review were permitted to undergo six cycles of docetaxel, and the aim was to explore the clinical benefit of combination therapy with a NGARI and docetaxel. The percentages of patients treated with docetaxel in the ARCHES, ENZAMET, TITAN, and ARASENS trials were 17.8%, 44.7%, 10.7%, and 100%, respectively. Our NMA tried to report the indirect OS comparisons of the three NGARIs based on treatment with docetaxel and ADT. Some previous N9MAs have reported the efficacy of these NGARIs in non-metastatic castration-resistant prostate cancer, but the optimal options for mHSPC are unknown [19,20]. Sathianathen et al. indirectly compared the efficacy of enzalutamide and apalutamide; however, the survival data from the ARCHES and ARASENS trials were immature at that time and had not been reported adequately [21]. Based on more mature survival data, we designed an NMA with the aim to establish a ranked order of treatments based on their efficacy, which provides more reliable information on the therapeutic approach for mHSPC than most previously published NMAs.
Second, an indirect comparison of the four trials revealed differences in the effect size on OS. Although all three NGARIs prolonged OS time, the results of the cumulative ranking plot showed the most optimal option. The SUCRA values for enzalutamide, apalutamide, and darolutamide were 70.08%, 66.97%, and 62.8%, respectively (Table 2). These results helped us rank the various treatment options. Enzalutamide might be the most optimal option in patients with mHSPC, followed by apalutamide and darolutamide. The results of the current analyses are based on most mature survival data and included an indirect comparison of darolutamide, which is consistent with the findings reported by Sathianathen et al. [21]. Our current NMA and previous NMAs employed SUCRA to assess the preference of treatments. The rank plot according to our NMA’s findings provided more reliable evidence to determine the therapeutic options regarding NGARIs. However, due to the lack of non-inferiority trials, subtle differences in efficacy between these treatments are unclear.
This current NMA is the first to perform subgroup analysis of the effectiveness of three NGARIs in patients with mHSPC who were treated with docetaxel. Docetaxel treatment for six cycles was used as a primary therapy for mHSPC > 30 years ago, which allowed a fixed duration of treatment with six cycles. An increasing number of trials have reported that docetaxel has an improved survival benefit in men with mHSPC [3,4]. Subsequently, addition of docetaxel to ADT became the SOC for patients with mHSPC to cure the high burden of metastatic disease [22]. Docetaxel was approved for the treatment of mHSPC as a SOC option which was used in the ENZAMET, TITAN, ARASENS and ARCHES trials. However, the size of effect on OS in the ARCHES trial is currently immature and not included as relevant data in this analysis as part of the subgroup of patients treated with docetaxel. The results of this subgroup analysis answered the question of whether addition of NGARIs as SOC, such as docetaxel and ADT, may improve survival outcomes in patients with mHSPC. In subgroup analysis, only darolutamide improved OS significantly. SUCRA showed that darolutamide had a 94.00% chance to be the best treatment option when combined with docetaxel. Moreover, the trials included in our NMA showed that the combination of docetaxel with enzalutamide or apalutamide did not improve OS (Fig. 4 and Supplementary Fig. 3A). These findings can be explained by the use of docetaxel, a type of taxane; it can inhibit androgen receptor (AR) nuclear translocation and downstream AR signal pathways [23]. Therefore, docetaxel combined with an AR inhibitor may not significantly improve or have an increased benefit for prostate cancer. This hypothesis might be the reason why darolutamide was ranked the last in the four trials. Because all patients in the ARASENS trial were treated with docetaxel, which differed from the other trials.
Finally, despite advancing research with several main observations was conducted by using the NMA-based approach, the findings of this NMA should be interpreted with caution considering its limitations. First, we conducted an indirect comparison, which cannot replace direct comparison adequately. Thus, the findings should be interpreted with caution. Moreover, there were differences in patient characteristics between the four trials, which might have led to differences in treatment effect. For example, in the ENZAMET trial, the patients of the control arm had undergone nonsteroidal anti-androgen therapy with ADT rather than ADT monotherapy. However, as a way of maximal androgen blockade, nonsteroidal anti-androgen therapy in combination with ADT may have a smaller survival benefit. Hence, we thought the difference in the control arm in the ENZAMET trial might slightly influence the results [24]. Moreover, the timing of docetaxel administration differed among the trials, which might become an influential factor in the indirect comparisons. Patients in the ARASENS trial were all treated with docetaxel, which might impact the findings. To explore the efficacy of darolutamide in addition to ADT versus ADT monotherapy in mHSPC, a trial, ARANOTE (NCT04736199), is currently recruiting patients. However, this trial is not expected to report its survival data. Therefore, what we need is to depend on the currently available data for the indirect comparison. Furthermore, the clinical characteristic of patients in the ARASENS trial did not include the group of high-volume disease or low-volume disease, which limited our confidence to compare the OS benefit in subgroup analysis.