Addition of Carboplatin to Cabazitaxel Promising for mCRPC

Paul G. Corn, MD, PhD

Paul G. Corn, MD, PhD

Cabazitaxel (Jevtana) in combination with carboplatin demonstrated an improvement in progression-free survival (PFS) in comparison with cabazitaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). Adverse events were more common with the combination regimen, but the doublet was generally well tolerated, according to findings from the phase I/II trial published inThe Lancet Oncology.

“The results of our study support the hypothesis that carboplatin added to cabazitaxel improves median progression-free survival and response in men with metastatic castration-resistant prostate cancer, and they show that the combination was safe and tolerable with appropriate antiemetic and growth factor support,” the study authors, led by Paul G. Corn, MD, PhD, of The University of Texas MD Anderson Cancer Center, wrote. They noted that this was the first study to establish the benefit of combining a platinum with a taxane for the treatment of mCRPC in a randomized, prospective design.

The open-label, randomized phase I/II trial investigated the combination of cabazitaxel and carboplatin in men with advanced prostate cancer across 2 sites, MD Anderson Cancer center and Karmanos Cancer Institute. The men had metastatic prostate adenocarcinoma, small-cell prostate carcinoma, or both and were required to have castration-resistant disease progression. Additionally, the men had an ECOG performance status between 0 and 2 and adequate organ function.

Patients were allowed to have previously received hormonal therapies, but prior treatment with cabazitaxel, carboplatin, or ≥2 chemotherapy regimens was not allowed. Further exclusion criteria included radiotherapy within 14 days of registration, major surgery or samarium-153 within 28 days, and strontium-89 within 12 weeks. Patients with uncontrolled incurrent disease, imminent complications from bone metastases, active secondary malignancies, or other serious illnesses were not eligible for enrollment. 

The investigators also looked at the effect of the aggressive variant prostate cancer phenotype on response. The aggressive variant prostate cancer criteria included 7 clinicopathologic features: histological evidence of small-cell prostate carcinoma, exclusive visceral metastases, predominant lytic bone metastases, bulky lymphadenopathy or primary tumor at diagnosis with a Gleason score of ≥8, low prostate-specific antigen (PSA) and high-volume bone metastases, elevated lactate dehydrogenase (LDH) or carcinoembryonic antigen (CEA), and short interval response at androgen deprivation therapy (ADT). Patients were considered to have the aggressive phenotype if they had at least 1 of these criteria.

The phase I portion of the trial investigated escalating doses of intravenous cabazitaxel plus carboplatin in a 3+3 design to determine the maximum tolerated dose for the combination. Cohort 1 were administered 20 mg/m²cabazitaxel plus AUC 3 mg/mL per min of carboplatin, cohort 2 received 20 mg/m²cabazitaxel plus AUC 4 mg/mL per min carboplatin, and cohort 3 received 25 mg/m²cabazitaxel plus AUC 4 mg/mL per min carboplatin.

Nine patients were treated in phase I with 3 in each cohort. No dose-limiting toxicities were reported, so the maximum tolerated dose was set as cabazitaxel 25 mg/m²plus carboplatin AUC 4.

Each patient developed at least 1 adverse event (AE), which were most commonly fatigue, anemia, nausea, and diarrhea. Grade 3 AEs included anemia in 2 patients and fatigue, thrombocytopenia, hypomagnesemia, diarrhea, hypokalemia, anorexia, and dehydration in 1 patient each. No grade 4 AEs were observed.

In the phase II portion of the study, 160 patients were randomized 1:1 to either cabazitaxel plus carboplatin (n = 81) or cabazitaxel alone (n = 79). Stratification was according to ECOG performance status, prior docetaxel treatment, response to docetaxel, and the presence of aggressive variant prostate cancer criteria.

Patients in either arm received 25 mg/m²of cabazitaxel and in the investigational arm this was combined with AUC 4 carboplatin given intravenously every 21 days. Treatment continued for up to 10 cycles until disease progression, unacceptable toxicity, or withdrawal from the study. Growth factor support and 5 mg prednisone twice daily was also given to all patients.

The primary endpoint of the phase II portion of the trial was investigator-assessed PFS. Secondary endpoints included the evaluation of PSA response, overall survival (OS), safety, and toxicity.

Baseline characteristics were similar between the 2 arms. More than 50% of patients in each arm (52% in cabazitaxel arm; 56% in combination arm) had criteria for the aggressive variant phenotype and more than 90% (91% and 93%, respectively) had bone metastases. Patients had received prior treatment for castration-resistant prostate cancer, including most commonly abiraterone acetate (Zytiga) in 53% of the single-agent group and in 69% of the combination group.

Patients were followed for a median of 31.0 months (range, 20.5-37.1). The median PFS was 7.3 months (95% CI, 5.5-8.2) in the combination arm compared with 4.5 months (95% CI, 3.5-5.7) with cabazitaxel alone (HR, 0.69; 95% CI, 0.50-0.95;P= .018).

By subgroup analysis, patients with an ECOG performance status of 0 (HR, 0.36;P= .0027), no prior docetaxel treatment (HR, 0.62;P= .014), and those who had aggressive variant criteria (HR, 0.58;P= .013) especially favored treatment with the combination.

The median OS was 18.5 months (95% CI, 16.7-21.9) in the combination group versus 17.3 months (95% CI, 13.8-21.0) in the cabazitaxel-alone arm (HR, 0.89; 95% CI, 0.63-1.25;P= .50).

PSA declines >50% were seen in 61.7% and 40.9% of patients with evaluable PSA concentrations in the combination and monotherapy arms, respectively.  

The median duration of treatment was 4.9 months in the combination arm versus 3.8 months with cabazitaxel alone. Twenty-one percent of patients in the combination arm required a dose reduction of cabazitaxel and 4% needed a reduction in carboplatin, whereas 4% of patients needed a dose reduction in the cabazitaxel monotherapy arm.

The most common grade 3-5 AEs observed in phase II included fatigue (20% with the combination vs 9% with cabazitaxel alone), anemia (23% vs 4%), neutropenia (16% vs 4%), and thrombocytopenia (14% vs 1%). Serious AEs were reported in 40% of patients in the combination group and in 22% of the monotherapy arm, which were most frequently dehydration, pain, neutropenia, and neutropenic fever.

Twelve percent of patients discontinue treatment from the combination arm due to AEs compared with 10% in the single-agent arm. The most common events leading to discontinuation were fatigue, hematuria, and cystitis, and all resolved upon treatment cessation.

Post-hoc analyses were completed on 133 tissue samples from 96 patients to review the effect of the aggressive variant phenotype. Of 56 tumors assessed by immunohistochemistry, 46% were considered positive for the aggressive variant molecular signature.

Among these patients, the median PFS was 7.5 months (95% CI, 4.4-9.6) in those treatment with the combination compared with 1.7 months (95% CI, 1.3-not available) in those treated with cabazitaxel alone (P= .017). The estimated median OS was 20.2 months (95% CI, 13.3-37.2) with the combination versus 8.5 months (95% CI, 4.8-not available) with cabazitaxel alone (P= .0002).

The median estimated PFS (6.5 vs 6.3 months, respectively;P =.38) and OS (21.5 vs 21.7 months;P= .702) was similar between the treatment arms for patients with the molecular signature.

The study authors suggested that the molecular signature could potentially be used clinically as a biomarker of resistance to androgen-targeting therapies and platinum-based chemotherapy, although further verification was needed.

Following the results of the study, a phase III trial is planned to further validate the combination regimen in comparison with cabazitaxel alone as a treatment option for men with mCRPC among those who do or not do demonstrate the aggressive variant prostate cancer molecular signature.

Reference:

Corn PG, Heath EI, Zurita A, et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1—2 trial [published online September 9, 2019].Lancet Oncol.doi: 10.1016/S1470-2045(19)30408-5.