medwireNews: Phase I/II research published in The Lancet Oncology shows that combining cabazitaxel with carboplatin has the potential to prolong progression-free survival (PFS) in men with metastatic castration-resistant prostate cancer (mCRPC).
“The improvements in outcomes with cabazitaxel and carboplatin in men were clinically meaningful, particularly in men with aggressive variant prostate cancer [AVPC] features, and the combination was safe and tolerable,” say Ana Aparicio (The University of Texas MD Anderson Cancer Center, Houston, USA) and colleagues.
None of the nine patients recruited to phase I experienced dose-limiting toxicities or grade 4 adverse events (AEs) with the combination of cabazitaxel 20–25 mg/m2 plus carboplatin AUC 3–4 mg/mL per min administered every 21 days, with the highest dose of each drug selected as the phase II dose.
Aparicio et al report that over a median follow-up of 31.0 months, median PFS was 7.3 months for the 81 men who were randomly allocated to receive the combination treatment in phase II, which was significantly longer than the median PFS of 4.5 months for the 79 men treated with cabazitaxel alone. This equated to a hazard ratio (HR) for progression or death of 0.69 in favor of combination treatment.
However, the median overall survival (OS) did not differ significantly between patients given cabazitaxel with and without carboplatin, at 18.5 and 17.3 months, respectively.
The researchers note that AEs “were more common with the combination,” with, for instance, higher rates of grade 3–5 anemia (23 vs 4%), fatigue (20 vs 9%), neutropenia (16 vs 4%), and thrombocytopenia (11 vs 1%) in the combination than cabazitaxel alone arm.
And a greater proportion of patients who received the combination reported serious AEs, at 40%, versus 22% of cabazitaxel-treated patients.
But AEs leading to treatment discontinuation – most commonly fatigue, hematuria, and cystitis – occurred in a comparable 12% and 10% of patients given cabazitaxel with and without carboplatin, respectively, and there were no treatment-related deaths in either study arm.
“To our knowledge, our study is the first to establish the benefit of combining a platinum agent with a taxane agent in [mCRPC] using a randomised, prospective trial design,” say the study authors, although they acknowledge that “the observed improvement was modest in the overall population.”
Additional analysis indicated, however, that combination treatment especially benefited men with one of seven AVPC features, such as small-cell prostate carcinoma, exclusively visceral metastases, primarily lytic bone metastases, and bulky lymphadenopathy or a primary tumor Gleason score of at least 8.
And indeed, individuals with tumors positive for an AVPC-associated molecular signature – either by immunohistochemistry or circulating tumor DNA analysis – derived “clinically meaningful improvements” from combination treatment versus cabazitaxel alone in PFS (6.0 vs 2.2 months) and OS (17.4 vs 9.9 months), the team reports.
By contrast, men with tumors lacking the signature had no significant improvement in median PFS (6.0 vs 5.9 months) or OS (18.9 vs 22.2 months) with the addition of carboplatin to cabazitaxel.
In an accompanying comment, Emmanuel Antonarakis, from Johns Hopkins University in Baltimore, Maryland, USA, postulates that “[t]hese data not only suggest that patients with [mCRPC] without molecular aggressive variant prostate cancer features might not require the addition of carboplatin to cabazitaxel, but also that such patients might be harmed by the added side-effects of combination chemotherapy.”
By Hannah Kitt
medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group
Lancet Oncol 2019; doi:10.1016/S1470-2045(19)30408-5
Lancet Oncol 2019; doi:10.1016/S1470-2045(19)30497-8