Dataset Information

Combination Androgen Receptor Inhibition and Docetaxel in Metastatic Castration-sensitive Prostate Cancer: The Next Step in First-line Treatment?

ABSTRACT: The addition of docetaxel and abiraterone to androgen deprivation therapy (ADT) heralded a new era in the first-line treatment of metastatic castration-sensitive prostate cancer (mCSPC). Following the success of these combination regimens, 3 new trials presented data on using enzalutamide or apalutamide in men with mCSPC, which showed similar success. These seminal trials collectively established the addition of docetaxel, enzalutamide, apalutamide, or abiraterone to ADT as standards in the upfront treatment of mCSPC. Notably, a subset of patients in these more recent trials were treated with a combination of docetaxel, ADT, and androgen receptor signaling inhibitors or maintenance androgen receptor signaling inhibitors after docetaxel and ADT that provided an initial glimpse into the efficacy of these triplet or maintenance strategies. We discuss the implications of these recent findings and place them in context of the current mCSPC treatment landscape.

SUBMITTER: Adashek JJ

PROVIDER: S-EPMC9212901 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Combination Androgen Receptor Inhibition and Docetaxel in Metastatic Castration-sensitive Prostate Cancer: The Next Step in First-line Treatment?

Adashek Jacob J JJ Reed Jarred P JP Tandon Ankita A Freedland Stephen J SJ Posadas Edwin E Bhowmick Neil N Chung Leland W LW Freeman Michael M Figlin Robert A RA Gong Jun J

Clinical genitourinary cancer 20200511 6

The addition of docetaxel and abiraterone to androgen deprivation therapy (ADT) heralded a new era in the first-line treatment of metastatic castration-sensitive prostate cancer (mCSPC). Following the success of these combination regimens, 3 new trials presented data on using enzalutamide or apalutamide in men with mCSPC, which showed similar success. These seminal trials collectively established the addition of docetaxel, enzalutamide, apalutamide, or abiraterone to ADT as standards in the upfr ...[more]

PMID: 32631766

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Project description:Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR]=1.61, 95% confidence interval [CI]=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95% CI 0.74-1.46, p=0.8) or PSA response (odds ratio=1.14, 95% CI=0.65-1.99, p=0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.16, 95% CI=0.06-0.46, p<0.001) and PFS (HR=0.31, 95% CI=0.12-0.80, p=0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR=1.93, 95% CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95% CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial. PATIENT SUMMARY: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker.

Project description:BackgroundMultiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS.MethodsData from 1050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were evaluated. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment, 6 week and progression serum assays for T, A and DHEA were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Changes in T, A and DHEA levels from baseline to 6 weeks were calculated as the ratio of 6-week over baseline. The proportional hazards model was used to assess the prognostic significance of changes in T, A, and DHEA from baseline to 6 weeks in predicting OS adjusting for known prognostic factors.ResultsMedian baseline values for T, A, and, DHEA were 1.0, 13.5, and 8.1 ng/dL respectively while 6 week levels were 0.64, 7.0, and 6.8 ng/dL respectively. Median OS for low testosterone decline is 20.9 months vs 26.3 months for high testosterone decline. In multivariable analysis including known prognostic variables, change in testosterone levels was independently associated with greater OS; the hazard ratio for death with each unit increase in the 6-week/baseline ratio is 1.02 (95% CI = 1.01-1.03, p = 0.001). Decline in A and DHEA were not significant predictors of OS. In multivariable analysis change in the serum changes did not predict PFS however the ratio of T at 6-weeks over baseline was prognostic of ≥50% decline in PSA with an odds ratio of 0.93 (95% CI = 0.85-0.98, p-value = 0.039).ConclusionsDeclines in testosterone during docetaxel treatment is associated with a longer survival, consistent with a favorable prognostic significance of higher serum androgens in the CRPC.

Project description:PurposeRecently, docetaxel treatment of metastatic prostate cancer patients shifted towards the hormone-sensitive stage of the disease. There are contradictive reports on differences in toxicity of docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) patients. Possible differences in toxicity might be attributed to different pharmacokinetics (PK) in the two patient populations.MethodsPatients with mCRPC or mHSPC and a standard indication for docetaxel treatment were included in the study. All patients had suppressed serum testosterone levels (≤ 0.5 ng/mL or 1.73 nmol/L). Venous blood samples were obtained at the first docetaxel treatment, until 48 h after infusion. Plasma concentrations of docetaxel, unbound docetaxel and docetaxel metabolites were measured using validated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) assays and compared between the two groups. Moreover, serum levels of docetaxel transporting α1-acid glycoprotein were measured and docetaxel toxicity recorded.ResultsA total of ten mCRPC and nine mHSPC patients were included in the study. The two cohorts differed in the number of prior treatments and opiate use, which were higher for mCRPC patients. The docetaxel PK was not different between mCRPC and mHSPC patients, with areas under the plasma concentration versus time curve (AUC0-48) 1710 [coefficient of variation (CV) 28.4%] and 1486 (CV 25.2%) ng/mL*h (p = 0.27), respectively. Also, the PK profile of unbound docetaxel, M1/M3, M2 and M4 metabolites were similar in both groups. Docetaxel doses were reduced in 50% of the mCRPC patients and 11% of the mHSPC patients.ConclusionThe PK profile of docetaxel was similar in mCPRC and mHSPC patients. Therefore, possible differences in toxicity between mCRPC and mHSPC patients cannot be explained by differences in docetaxel PK in our study population. These results suggest that treatment adaptations are not recommended in the new population of patients with mHSPC.

Dataset Information

Combination Androgen Receptor Inhibition and Docetaxel in Metastatic Castration-sensitive Prostate Cancer: The Next Step in First-line Treatment?

Publications

Combination Androgen Receptor Inhibition and Docetaxel in Metastatic Castration-sensitive Prostate Cancer: The Next Step in First-line Treatment?

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