Real-world effectiveness of third-line cabazitaxel in patients with metastatic castration-resistant prostate cancer: CARD-like analysis of data from a post-marketing surveillance in Japan

Prostate cancer (PC) is one of the most common types of cancer among men; age-standardized rate of PC worldwide was 30.7 per 100,000 person-years in 2020 [1]. Despite favourable response to initial treatment, many men with PC then experience progression due to treatment resistance [2]. Metastatic disease is the leading cause of death from PC, with an overall survival (OS) of 16–18 months on average after disease progression [2, 3].

Androgen deprivation therapy (ADT) with castration remains the standard initial treatment for PC [2] and docetaxel chemotherapy has been the standard first-line treatment for metastatic PC since 2004 [2, 4]. Androgen receptor-axis-targeted therapies (ARATs)¹, such as abiraterone or enzalutamide, are newer ADTs that are now commonly used for first-line treatment of metastatic castration-sensitive PC (mCSPC) as well as metastatic castration-resistant PC (mCRPC) [5, 6]. Subsequent treatment options for mCRPC have expanded beyond the first line to include either an alternative ARAT or cytotoxic taxane-based chemotherapy, such as cabazitaxel [7]. With increasing use of ARATs and taxanes in earlier lines of treatment, cross-resistance between therapies due to shared mechanisms of resistance [8] has emerged as an impediment in treatment of mCRPC at later lines. Sequential use of ARATs for the treatment of mCRPC is frequent in clinical practice [9, 10], despite guidance in Europe and the US cautioning against such use [11, 12].

Cabazitaxel was approved for treatment of CRPC in patients who were previously treated with docetaxel and is recommended at 20 or 25 mg/m² in combination with oral prednisolone [13‐15]. The CARD trial was a randomised clinical trial of mCRPC patients who have previously received docetaxel and experienced disease progression within 1 year on an ARAT, who then received either 25 mg/m² cabazitaxel or an alternative ARAT [16]. The CARD trial reported significantly improved imaging-based progression-free survival (PFS) and OS in patients receiving cabazitaxel compared with those receiving an alternative ARAT [16].

Subsequently, de Wit et al. have applied these findings to a real-world data analysis of a CARD-like cohort using a global oncology database and found that the results from the CARD trial reflect the characteristics of patients in real-world clinical practice [9]. Given that the CARD trial suggested that cabazitaxel is more effective than an alternative ARAT, this study aims to retrospectively confirm its effectiveness in real-world patients and whether the results from de Wit’s real-world analysis [9] also apply to Japanese patients. This study also aims to identify any patterns of cross-resistance to treatment arising from sequential use of ARATs or taxane-based chemotherapies in a real-world population, by applying the analysis from the CARD trial to a real-world dataset from a Japanese post-marketing surveillance (PMS) of cabazitaxel [17].

Real-world evidence has been gaining regulatory acceptance as drug discovery, development, and translation evolves [18]. New approaches are enabling collection of better post-marketing data and translation of that data to healthcare practice. Efforts to validate results from clinical trials in the real-world setting, particularly for breakthrough treatments that address serious unmet medical needs, are of paramount importance.

In the CARD clinical study, the frequency of adverse events (AEs) was similar between the cabazitaxel and the second alternative ARAT arms, though AEs leading to treatment discontinuation were reported more frequently with cabazitaxel [16]. Cabazitaxel led to significantly improved imaging-based PFS (8.0 months vs 3.7 months, respectively) and OS (13.6 months vs 11.0 months, respectively; risk of death, HR 0.64, 95% CI 0.46–0.89, P = 0.008) compared with the alternative ARAT [16]. Furthermore, patients receiving cabazitaxel had improved quality of life compared with those receiving a second alternative ARAT [19].

In this PMS study, the TTF of the third-line therapy for patients receiving an alternative ARAT was half of that for patients receiving cabazitaxel (58 days vs 109 days, respectively). Whereas imaging-based PFS was assessed as the primary endpoint in the CARD trial, TTF is generally considered to be more appropriate as a measure of effectiveness in clinical practice, because patients may discontinue therapies due to toxicity despite lack of disease progression, in daily practice. The median TTF of cabazitaxel in this study was 109 days and the median PFS in the CARD trial was 4.4 months [16]. There are several possible reasons why the effectiveness of cabazitaxel was worse in this study compared with the CARD trial. First, TTF can be expected to be shorter than PFS because TTF incorporates a wider range of events (e.g. treatment discontinuation due to AEs). In that regard, the frequency of ADRs leading to discontinuation in the cabazitaxel arm of this real-world study was non-negligeable at 14.6% (Additional file 1: Table S1). Second, a lower dose of cabazitaxel (< 25 mg/m²) was more frequently used in this study than in the CARD trial (81.4% vs 21.4%, respectively) [16]. Furthermore, the patient cohort in this PMS (both cabazitaxel and second ARAT arms) had more advanced disease than the CARD cohort in terms of Gleason score and serum PSA level. In fact, the OS of the cabazitaxel arm in the real-world was shorter (median, 326 days; 95% CI, 267– not estimable) than that in the prospective CARD trial (median, 413 days; 95% CI, 350–532) [16], which might be attributed to the more advanced disease of the former or lower exposure to cabazitaxel in clinical practice than in the trial. Despite the above differences, the effectiveness of cabazitaxel relative to a second ARAT in this PMS study was in line with that of the CARD trial [16].

The CARD trial enrolled patients who progressed within 1 year on the first ARAT [16]. We emphasize that in this PMS study, only 5 out of 561 patients received the first ARAT for > 1 year. Among those who received the first ARAT for a year or less, only 20% received the therapy for more than 6 months (Additional file 2: Fig. S1) with a median TTF less than 100 days (Table 2). In the CARD trial, 50% of patients received their first ARAT for 6–12 months [16], and another study reported a median PFS of 6.6 months in a patient population receiving their first ARAT following docetaxel [5]. Compared with the patient population of these studies, the patients analysed in this PMS study appears to have been more resistant to ARAT. Nonetheless, TTF of the cabazitaxel arm was longer than that of the second ARAT arm with HR (95% CI) of 0.339 (0.279–0.413) favouring cabazitaxel.

Molecular mechanisms of cross-resistance between ARAT treatments include androgen receptor (AR) splice variants, AR overexpression, AR mutations, and glucocorticoid upregulation [20]. Cell-based analysis has demonstrated that docetaxel confers cross-resistance to cabazitaxel and that this is mediated by increased expression of ABCB1 [21]. Similar analysis also suggested the existence of intra cross-resistance within ARATs or taxanes, whereas inter cross-resistance between these drug classes does not develop in practice [22]. Prospective randomised clinical trial studies have confirmed cross-resistance between abiraterone and enzalutamide and suggested that abiraterone followed by enzalutamide may provide greater benefit compared with the opposite sequence [8]. In the present analysis, cross-resistance between the first ARAT and the second alternative ARAT was evident, whereas it was unclear which sequencing order was more beneficial in the patient population from this PMS (Additional file 2: Fig. S2a and S2b). Nevertheless, the clinical benefit of cabazitaxel following docetaxel and an ARAT was evident, further supporting the sequential use of an ARAT and cabazitaxel for the treatment of mCRPC in the real-world.

In this analysis, more than half of the CARD-like cohort received sequential ARAT, consistent with recent global real-world studies showing frequent sequential use of ARAT [9, 10]. Our study suggests that patients who progress within 1 year on their first ARAT treatment may be more likely to respond to cabazitaxel than to a second alternative ARAT in a subsequent treatment, confirming the findings of the CARD clinical trial in a real-world Japanese patient population.

Consistent with the CARD trial, cabazitaxel demonstrated superior effectiveness over a second alternative ARAT in a real-world patient population in Japan, despite the population having more advanced disease status and a lower dose of cabazitaxel being more frequently administered, than in the CARD trial. Cross-resistance between the first ARAT and the second alternative ARAT was evident.