Cabazitaxel + carboplatin in treatment of mCRPC


A newly published article in Lancet Oncology has suggested that “taxane–platinum combinations have a clinically beneficial role in advanced prostate cancer”.

The new paper by Corn et al. reports data from the randomized, open-label, Phase II portion of a Phase I/II trial in which men with metastatic, castration-resistant prostate cancer (mCRPC) were randomized to treatment with either intravenous carbazitaxel (Jevtana) alone or with carbazitaxel + carboplatin. Earlier, smaller, non-randomized trials and retrospective data analyses have also suggested the possibility that taxane + carboplatin combinations could be effective in the treatment of men with mCRPC, but this appears to be the first time that this has been confirmed in a reasonably large, randomized, Phase II trial.

Men were initially enrolled in this trial between 2012 and 2015. Nine men initially completed the Phase I stage of the rial (to assess appropriate doses of the drug combination and the safety factors in giving these two drugs together).
A total of 160 patients were then randomized to one or other of the two possible treatments. All patients were also treated with growth factors and with oral prednisone. Here are the core results reported by Corn et al.:
  • Average (median) follow-up was 31.0 months
  • The median progression-free survival (PFS) times were
    • 4.5 months for the patients treated with cabazitaxel
    • 7.3 months for the patients treated with cabazitaxel + carboplatin
  • This difference in PFS was statistically significant (hazard ratio [HR] = 0.69, p = 0.018).
  • In the phase II study, the most common grade 3–5 adverse events were:
    • Fatigue in 7/79 men [9 percent] treated with cabazitaxel group vs 16/81 men [20 percent] treated withcabazitaxel + carboplatin)
    • Anemia (3/79 [4 percent] vs 19/81 [23 percent])
    • Neutropenia (3/79 [4 percent] vs 13/81 [16 percent])
    • Thrombocytopenia (1 [1 percent] vs 11 [14 percent]).
  • There were no treatment-related deaths reported in this study.

Corn et al. conclude that:

Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane–platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned.

It will be apparent to many patients that exactly how the patients enrolled in this trial had been treated before they entered the trial could be highly relevant to the trial data. The inclusion criteria for the trials made the following four statements (among many others):
  • Castration-resistant prostate cancer; patients must have surgical or ongoing chemical castration (with luteinizing-hormone-releasing hormone [LHRH] agonists or LHRH antagonists), with a baseline testosterone level < 50 ng/dL
  • Metastatic disease; patients must have evidence for metastatic prostate cancer by bone scan and/or CT/magnetic resonance imaging (MRI) (i.e., soft tissue, visceral, lymph node); if lymph node, visceral and/or soft-tissue metastases are the only evidence of metastasis, at least one lesion must be ≥ 1.5 cm in diameter
  • Patients may have received prior treatment with androgen ablative therapies (such as bicalutamide, ketoconazole, diethylstilbestrol [DES], abiraterone, Xtandi, ARN-509) and/or “targeted” therapies (such as tyrosine kinase inhibitors); androgen ablative therapies must be discontinued ≥ 3 days prior to initiation of study treatment with the exception of abiraterone and/or enzalutamide, which may be continued during study treatment per the practice preference of the treating physician; patients who are predicted to benefit from an antiandrogen withdrawal response should be tested for this possibility before being considered for eligibility to this study; targeted therapies must be discontinued >= 2 weeks before initiation of study treatment
  • Both chemotherapy-naive and patients previously treated with chemotherapy are eligible; chemotherapy pretreated patients may have received a maximum of two prior systemic cytotoxic chemotherapies completed at least 3 weeks prior to initiation of study treatment

What seems probable at this point in time is that the combination of cabazitaxel + carboplatin is effective in certain specific subsets of patients with mCRPC. We assume that the proposed Phase III trial will be designed to attempt to stratify patients by such subsets. As yet the protocol for the proposed Phase III trial does not appear to be available on ClinicalTrials.gov.

2 Responses

  1. This a very interesting and helpful study!

    We have run across genitourinary MED/ONCs who believe that mixing Jevtana with carboplatin makes both less effective because there is not enough of either to have a result. In other words, they prefer to do all taxane based or all carboplatin.

    This study just shows that the combo works. The question would be whether higher doses of either would work better. That would take a second study with various arms. One wonders if Sanofi would stretch to that; I plan to dialog with Paul Corn to ask.

    And — as our Sitemaster correctly notes — carboplatin is best employed for men with strange/weird adenocarcinomic disease and for men whose disease has morphed towards small cell/neuroendocrine. We have one guy considering this right now!

    Serendipitously, two of our AnCan advanced prostate cancer regulars have appointments with Dr. Corn today. He is wonderful, compassionate and very smart doctor. We frequently refer men to him.

  2. M. D. Anderson Cancer Center is also running a trial of this chemotherapy combination ± olaparib (a PARP inhibitor) as maintenance afterward.

    While the side effects are increased by adding carboplatin, it may (or may not be) exclusively effective in those patients with genomic alterations in DNA damage repair (DDR) pathway genes. They are testing for such alterations at baseline and after carboplatin. If carboplatin does indeed only benefit those with DDR alterations, it may allow for better patient selection for the more toxic combination and allow for maintenance with a PARP inhibitor (which is also known to be beneficial in such cases).

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