Purpose
Treatment for poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting.
Patients and Methods
This multicentre, randomised, open-label, phase 2 trial recruited patients with ARPI-naïve mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1:1 to receive cabazitaxel plus prednisone (Group A) or physician's choice of enzalutamide or abiraterone plus prednisone (Group B) at standard doses. Patients could cross-over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as PSA response ≥50%, radiographic response, or stable disease ≥12 weeks).
Results
95 patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in Group A versus B (80% vs 62%, p=0.039). Overall survival was not different between Group A and B (median 37.0 vs 15.5 months, HR=0.58, p=0.073) nor was time to progression (median 5.3 vs 2.8 months, HR=0.87, p=0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% vs ARPI 0%), diarrhea (9% vs 0%), infection (9% vs 0%) and fatigue (7% vs 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, p < 0.001; HR = 4.03, p < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, p < 0.001).
Conclusions
Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naïve poor prognosis mCRPC. CtDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.
A plethora of compounds including the frequently used androgen-receptor pathway inhibitors (ARPI) and the cytotoxic agents of the taxane class built the current mainstay of systemic treatment for metastatic castration-resistant prostate cancer (mCRPC). However, precision medicine is still at its onset since most therapeutic options are indicated for an unselected population. Until molecularly tailored, and probably tumour-agnostic, concepts are generally available, the identification of clinically defined subgroups benefitting most from a particular systemic protocol is an important step to overcome the “dry spell.” For instance, clinically classified aggressive variants of prostate cancer have demonstrated a favourable response to platinum-based therapy in the past.
Annala et al. present a prospective multicentre phase-2 trial which randomised males with poor prognosis, ARPI-naive mCRPC to receive either cabazitaxel or an ARPI (abiraterone or enzalutamide). Poor prognosis was defined as any of the following criteria: liver metastasis, time to CRPC < 12 months, or the presence of at least four of the following six factors: LDH > upper limit of normal (ULN), Eastern Cooperative Oncology Group performance status (ECOG PS) 2, visceral metastasis, serum albumin ≤ 4g/dl, ALP > ULN or < 36 months from the start of the initial androgen deprivation therapy to the time of study enrolment. The primary endpoint was the clinical benefit rate (CBR) defined as PSA50 decline, radiographic response, or stable disease for 12 weeks at least. The study was prematurely closed after accrual of 95 of the planned 120 patients.
In total, CBR was higher in cabazitaxel-treated patients than in APRIs (80% vs. 62%). Median follow-up was 21.9 months without differences in overall survival. While grade ≥ 3 toxicities were more common in cabazitaxel-treated patients (50% vs. 10%), dose delays were necessary for 24% and 6% of men receiving cabazitaxel or ARPI, respectively. Previous docetaxel exposure (26% of patients) was associated with a shorter time to progression. Baseline ctDNA fraction above the cohort median predicted a decreased overall survival and time to progression, whereas ctDNA increase correlated with reduced time to progression. Of note, DNA damage repair defects were more abundant in this population compared to an unselected one (29% vs. 9%). Androgen receptor amplification was associated with a shorter time to progression equally in both treatments.
Interpretation of the findings of the study is hampered inter alia by the premature closure of the patient accrual. The clinical value of the primary endpoint is questionable since the observed advantages of cabazitaxel did not translate into survival benefits. Furthermore, observed higher toxicity of cabazitaxel is not counter-intuitive. All-in-all, the findings of this trial will probably not exert a significant impact on the therapy choice between cabazitaxel and ARPI. Further prospective comparative research is warranted to provide molecular-based individualised treatment in order to improve outcomes for males with mCRPC.