Docetaxel Rechallenge Research Articles

Safety of Docetaxel in a Patient with Metastatic Castration-Resistant Prostate Cancer After Kidney Transplantation: A Case Report

There are limitations in treating advanced prostate cancer (PC), especially castration-resistant (CR) cases, in renal transplant recipients (RTRs). We describe the case of RTR with metastatic CRPC (mCRPC) treated with docetaxel. A 60-year-old man with end-stage renal disease due to autosomal-dominant polycystic kidney disease (ADPKD) underwent living-related kidney transplantation. A year later, he was diagnosed with PC (prostate-specific antigen level: 998 ng/mL). Prostate biopsy revealed prostatic adenocarcinoma with a Gleason score of 4 + 4 = 8. Radiographic examination revealed seminal vesicle invasion and multiple bone and lymph node metastases. Combined androgen blockade therapy was initiated; however, the patient was diagnosed with CRPC 6 months later. Triweekly docetaxel therapy was administered 28 months after diagnosis. The patient successfully completed 7 cycles of this therapy without major adverse events. However, after the 7th cycle, he developed a high fever caused by an infection of ADPKD-associated renal cysts. Therefore, docetaxel was discontinued, and enzalutamide was started, followed by abiraterone, but without any effect. We then introduced cabazitaxel but discontinued it because of hepatic dysfunction. Hence, the patient underwent a docetaxel rechallenge. He was administered the PEGylated form of the recombinant human granulocyte colony-stimulating factor for neutropenia prophylaxis. After 6 cycles of rechallenge docetaxel therapy, the patient accidentally fell, resulting in a cervical spine fracture and subsequent death due to respiratory failure. Docetaxel can be safely delivered to patients with CRPC after renal transplantation who are taking oral immunosuppressants. It can be a good treatment option for them.

Outcomes of post-progression therapies in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) progressing after docetaxel (DOC): Real-world data from an Italian multicenter observational study (ECHOS trial).

171 Background: The introduction of DOC in mCSPC raises the issue concerning the best therapeutic strategy after pts’ progression. Different options are available: a switch strategy with an androgen receptor signaling inhibitor (ARSI), an alternative chemotherapy-based strategy based on cabazitaxel (CABA), or a re-challenge strategy by using DOC again. In this view, it could be of interest to describe the outcomes of post-progression strategies adopted in the real-world. From 2014, ECHOS multicenter study is collecting real world data from mCSPC pts in Italy. Here, we present post-progression preliminary findings of 568 pts treated with DOC and enrolled in the study within 31 December 2021. Methods: We reviewed the clinical records of the mCSPC pts treated with DOC in 34 Italian Institutions. For each pt we recorded pre- and post-DOC clinical history, baseline characteristics, treatment details and clinical outcomes. Results: Among the 568 pts, after a median follow-up of 22 mos, 389 pts experienced disease progression and 227 died. The progression occurred after a median of 10.4 mos (range 0.3-62.1). Among the progressed pts, 47 did not received further active treatment, while 342 received at least one systemic treatment after progression. The most frequent post-progression treatment was ARSI (73.1%), followed by CABA (19%), combination of ARSI and PARP inhibitors within clinical trials (2.6%), DOC re-challenge (2.1%), platinum-based chemotherapy (1.8%), and radium 223 (0.9%). The outcomes of the first-line agents and the number of subsequent administered life-prolonging agents (LPA) are described. The length of disease control obtained with DOC influenced the duration of first post-progression therapy: in pts who progressed after DOC within 10.4 mos, the duration was significantly shorter than in pts with later disease progression (5.9 mos vs 9.8 mos, p < 0.0001). Noteworthy, pts with more aggressive disease leading to a faster progression received more frequently CABA than ARSI: disease progression after DOC in CABA group and in ARSI group occurred with a median of 9.1 mos and 13.2 mos, respectively (p = 0.002). Conclusions: This is one of the largest real-world report on the outcomes of first post-progression therapies after DOC in mCSPC pts. We showed that ARSI-based therapy is the most common strategy adopted after DOC progression. Our findings suggested a different first post-progression strategy according to the time of post-DOC progression onset. [Table: see text]

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castration-sensitive prostate cancer.

To assess the effectiveness of docetaxel rechallenge (DR) for metastatic castration-resistant prostate cancer (mCRPC) following chemohormonal therapy for metastatic castrate-sensitive prostate cancer (mCSPC). Additionally, we sought to define clinical factors predicting treatment response. Retrospective analysis of men treated with docetaxel for mCSPC and then rechallenged in the mCRPC setting from four cancer centers in Ontario, Canada. Prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) following DR were evaluated. Fifty five patients were identified between 2015 and 2020. Prior to DR, 94.5% of patients received androgen-receptor axis targeted therapy, 20% received radium-223, and 1.8% received cabazitaxel. Among 54 evaluable patients, 27.8% had a PSA decline ≥50%. Median PFS was 4.1 months (95% CI, 2.1-4.8) and median OS from androgen deprivation therapy initiation was 38.3 months (95% CI, 32.9-41.0). A Gleason Score of ≥8 was an independent predictor of prolonged PFS (HR 0.32, 95% CI, 0.12-0.81; P=0.02). DR following chemohormonal therapy for mCSPC produced a meaningful PSA response in approximately one-quarter of patients, with relatively short PFS. The impact of Gleason Score on docetaxel response warrants further investigation.

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castrate-sensitive prostate cancer.

117 Background: Since docetaxel has been advanced to the metastatic castrate-sensitive prostate cancer (mCSPC) setting, there is a lack of evidence guiding its re-introduction upon castrate-resistant (CR) progression. We sought to identify clinical characteristics and outcomes of patients subjected to docetaxel rechallenge (DR) following prior docetaxel exposure in the mCSPC realm. Methods: Patients rechallenged with docetaxel following treatment in the mCSPC setting were identified from three academic centres in Ontario, Canada. Retrospective chart reviews were performed to identify clinical, treatment and outcome variables. Results: Of the 45 patients with DR initiated between 06/2015 and 07/2020, the median age was 65, 60% had a Gleason score of ≥8, and 64% had an ECOG of ≤1. 56% had bone only metastasis, 4% lymph node only metastasis, 29% bone and lymph node metastasis, and 11% had visceral metastasis. In the mCSPC setting, 98% of patients received 6 cycles of docetaxel with 13% requiring dose delays. Of 43 informative patients, all had a PSA response to chemohormonal therapy. 91% achieved at least a 50% PSA response (PSA50), of which 40% had a 50-89% PSA reduction and 51% had a ≥90% PSA reduction. 29% of patients obtained a PSA nadir of &lt; 0.2 ng/mL. 16% had CR progression in &lt; 6 months, 56% in 6-12 months, and 28% in &gt; 12 months. DR was initiated after a median of 20.8 months (range 6.0-40.4) following the last dose of docetaxel for mCSPC, and was given as first line treatment for CR disease to 7%, second line to 51%, third line to 40%, and fourth line or beyond to 2% of patients. 69% of patients had received an androgen-receptor axis targeted therapy prior to DR, 18% radium 223, and 7% had received a trial drug. Notably, no patients had received cabazitaxel prior to DR. The median number of cycles of docetaxel received at rechallenge was 5 (range 1-11) with 18% of patients requiring treatment delays. 64% of patients stopped treatment due to progression, 16% due to side effects, 7% at the patient’s request, 7% due to completion of the planned number of cycles, and 6% due to death or other causes. Among 44 informative patients, 23% achieved at least a PSA50, with 18% having a 50-90% PSA reduction, and 5% having a ≥90% PSA reduction. The median time to progression (biochemical, radiographic, or death) was 2.3 months (95%CI 1.7-4.4) and the median overall survival was 11.0 months (95%CI 8.5-14.3). Conclusions: DR following exposure to docetaxel in the mCSPC setting resulted in a PSA50 in only around one quarter of patients. Both the median time to progression and overall survival were found to be short. With future investigations, we hope to identify clinical variables that will help predict which patients might benefit most from DR.

Docetaxel Rechallenge Improves Survival in Patients With Metastatic Castration-resistant Prostate Cancer: A Retrospective Study.

Docetaxel has been widely used in metastatic Castration-resistant Prostate Cancer (mCRPC) patients for decades. The purpose of the study was to evaluate the efficacy of docetaxel rechallenge in patients with mCRPC. We retrospectively compared patients who had received either first-line docetaxel and rechallenge after Androgen Receptor-axis Targeted therapies (ARAT), to those without rechallenge docetaxel. Multivariate cox-regression analysis was used to evaluate survival. Out of the 204 patients with mCRPC enrolled in the study, 24 patients received docetaxel rechallenge and 180 did not. The median overall survival was 50.11 months in the rechallenge group, as compared to 26.36 months in the non-rechallenge group (p of log rank=0.044). In the multivariate model, doxetaxel rechallenge was an independent risk factor for overall survival [hazard ratio (HR)=0.59, 95% confidence interval (CI)=0.32-0.99], together with the performance status score 2 (HR=2.46, 95%CI=1.32-4.58), hormone-sensitive state duration (HR=0.99, 95%CI=0.99-0.999), liver (HR=1.90, 95%CI=1.04-3.47) and brain metastases (HR=2.23, 95%CI=1.26-5.46). The advantage of rechallenge was addressed in the androgen receptor-axis-targeted (ARAT) non-responsive patients (HR=0.36, 95%CI=0.17-0.78). Adverse events were at 29.17% with Grade 3/4 neutropenia and at 20.83% with Grade 1/2 neutropenia in the docetaxel rechallenge group. The docetaxel rechallenge improved survival in patients with mCRPC failure of first-line docetaxel and subsequent abiraterone acetate or enzalutamide. Independent predictive factors for overall survival included i) the performance status, ii) hormone-sensitive state duration, iii) liver and iv) brain metastases. Patients non-responsive to ARATs will benefit from docetaxel rechallenge with regards to overall survival.

Pattern of prescribing after disease progression following upfront docetaxel in metastatic hormone-naïve prostate cancer within the UK: Results from a national study.

e19190 Background: Upfront docetaxel is now standard of care for men with newly diagnosed metastatic hormone naïve prostate cancer .After disease progression following upfront docetaxel, various treatment agents including further lines of chemo or novel hormonal agents are used but there have been no convincing evidence or consensus opinion about optimal sequencing. Methods: We have conducted a national study in the UK by approaching oncologists who treat prostate cancer with systemic therapies. The oncologists were requested to complete a web based survey about their treatment decisions . Aim were to gain an insight about current practice following docetaxel in the UK and to identify the various disease and patients related factors which could influence the decision-making process. Results: 114 oncologists were invited and 59 have responded, 80% clinical oncologist and 20% medical oncologists respectively. At the point of castrate-resistant disease progression, following docetaxel, abiraterone was most commonly used agents (63%), followed by Enzalutamide (29%), cabazitaxel (6%) and docetaxel re-challenge respectively. Time difference between finishing docetaxel and disease progression was considered the most important deciding factor to choose next agents. Other important factors as per responders were volume of the disease, patients current symptoms, co morbidities and site of metastases . Most oncologists felt initial PSA and Gleason scores were two least important deciding factors. Patients with low volume disease, 92 % oncologist preferred abiraterone or enzalutamide as opposed to chemotherapy. When disease progressed within 6 months of completion of docetaxel, only one fifth of responder would use further chemo in next line .After novel hormone agents, cabazitaxel was the most commonly prescribed agents. 81% of clinicians would consider re-challenging with Docetaxel at some point of treatment sequencing; of these the majority would only consider this after a minimal interval of 12-18 months following upfront treatment. Conclusions: Our study has demonstrated a wide variation of practice in the UK. It has reflected that the decision is complex and there is clear need for further evidence or guideline for sequencing.

Docetaxel rechallenge in metastatic castration-resistant prostate cancer: A retrospective, single-center study

PurposeTo assess the efficacy and safety of docetaxel rechallenge in the salvage setting in metastatic castration-resistant prostate cancer (mCRPC) patients.Materials and MethodsClinicopathologic data from patients treated with docetaxel rechallenge were collected from a single-center cancer registry. Among 227 patients who received first-line docetaxel for mCRPC between January 2011 and June 2019, 23 undergo rechallenge docetaxel after failure to androgen receptor targeting agents and/or cabazitaxel treatment. Endpoints included radiologic progression-free survival (PFS), treatment duration, and prostate-specific antigen (PSA) response and safety.ResultsOverall, 30%, 44%, 13%, and 13% of patients received docetaxel rechallenge as either the third, fourth, fifth, or sixth-line therapy, respectively, at a median of 23.6 months after stopping first-line docetaxel. With first-line docetaxel and rechallenge, median treatment duration was 6.4 and 3.3 months, respectively. With docetaxel rechallenge, PSA response was 35% (95% confidence interval [CI], 15% to 54%) and median PFS was 4.5 months (95% CI, 1.9 to 7.1 months). The median OS was 24.3 months (95% CI, 4.6 to 44.0 months). There were 7 severe adverse events (grade 3 or more) including anemia (8.7%), neutropenia, thrombocytopenia, leukopenia, diarrhea, and nausea (4.3% each).ConclusionsDocetaxel rechallenge showed meaningful anti-tumor activity with acceptable toxicity in heavily pretreated patients with mCRPC.

Efficacy and Prognostic Factors of Docetaxel Rechallenge on Metastatic Castrationresistant Prostate Cancer Patients

Efficacy and Prognostic Factors of Docetaxel Rechallenge on Metastatic Castrationresistant Prostate Cancer Patients

Impact of new agents (NAs) on survival of metastatic castration-resistant prostate cancer (mCRPC) patients (pts): A single-Institution retrospective analysis.

323 Background: Until few years ago, docetaxel (DOC) was the only agent able to significantly prolong overall survival (OS) of mCRPC pts: at the time of disease progression, other drugs without any survival benefit (mitoxantrone, vinorelbine, cyclophosphamide) or DOC re-challenge (DOC-re) in selected cases could be proposed. In the last years several NAs [abiraterone (AA), cabazitaxel (CAB), enzalutamide (ENZ), radium 223(RA223)] have been introduced in the clinical practice since they demonstrated an OS improvement. Moreover, a hypothetical cumulative OS advantage could derive from their sequential use. The present report is aimed to assess the impact on NAs on mCRPC pts’ OS in the daily clinical practice. Methods: We retrospectively evaluated all mCRPC pts treated in our Institution from 02/2002 to 06/2015 and recorded their medical history, anticancer treatments and survival outcomes. For the purpose of the present study, we consider pts who never received at least one NA (group A) and pts who received at least one NA (group B). To avoid selection bias due to a fast performance status worsening preventing further treatments, we consider only pts who received at least one agent after first line progression. For the OS analysis we considered the start of mCRPC first line. Results: We selected a consecutive series of 212 pts: 80 not treated (Group A) and 132 treated (Group B) with NAs. In the Group A 50 pts received first-line DOC followed by DOC-re only, while the remaining 30 pts received also agents different than DOC. In the group B 78, 35, and 19 pts received one, two, and three NAs, respectively. Group A pts were significantly younger and had higher baseline levels of PSA and lactate dehydrogenase (LDH). The OS was significantly longer in Group B than in Group A (36.0 vs 19.6 mos, p &lt; 0.0001). The impact of NAs use on OS was confirmed at the multivariate analysis comprising the other factors which significantly affected OS (hemoglobin, LDH, alkaline phosphatase, pain, performance status, PSA). Conclusions: Although the limitation due to its retrospective nature, our analysis confirms that the introduction of NAs in the daily clinical practice led to an OS improvement.

A randomised phase II trial of docetaxel versus docetaxel plus carboplatin in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial

BackgroundDocetaxel is standard first-line chemotherapy for patients with metastatic castration–resistant prostate carcinoma (mCRPC). Docetaxel re-challenge has never been tested in a prospective randomised controlled study. As some studies support the addition of carboplatin to docetaxel, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel re-treatment in docetaxel pre-treated mCRPC patients. MethodsPatients with mCRPC with a progression-free interval of ≥3 months after initial docetaxel treatment were randomised between docetaxel 75 mg/m2 or docetaxel 60 mg/m2 plus carboplatin AUC4. The primary end-point was progression-free survival (PFS; PSA/RECIST). ResultsOwing to insufficient recruitment, the study was discontinued early after inclusion of 75 patients (targeted 150) PFS and overall survival (OS) were comparable between both groups (median PFS 12.7 months (95% CI 9.9–17.5 months) with docetaxel monotherapy and 11.7 months (95% CI 8.5–21.0 months) with combination therapy (p = 0.98); OS 18.5 months (95% CI 11.8–24.5 months) versus 18.9 months (95% CI 16.0–23.7 months) (p = 0.79). An interim analysis (SEQTEST) showed that the null hypothesis could already be excepted, and no significant difference between both study arms was expected if inclusion would be completed. The incidence of grade 3–4 infections and gastrointestinal side-effects was numerical higher in the carboplatin arm (p = 0.056). ConclusionThis early terminated study suggests no benefit from the addition of carboplatin to docetaxel re-treatment in patients with mCRPC, whereas the combination resulted in more toxicity. Re-treatment with docetaxel monotherapy appears to be feasible, save and effective for patients with mCRPC and an initial good response to docetaxel. Trial registrationNTR3070.

Efficacy of cabazitaxel (CABA) rechallenge in heavily-treated patients with metastatic castration-resistant prostate cancer (mCRPC).

5033 Background: Only 2 chemotherapies have shown an overall survival (OS) benefit in mCRPC: docetaxel (DOC) and CABA. In patients (pts) previously treated with a new hormonal therapy (NHT: enzalutamide or abiraterone), DOC and CABA, therapeutic options are limited. We previously reported some activity of DOC rechallenge in good responders to first-line DOC. We present here the results of a retrospective study evaluating the efficacy and safety of CABA rechallenge. Methods: Records of 70 mCRPC pts rechallenged with CABA were collected in 17 centers (France, Italy, UK, Austria). To be included, pts should have previously received DOC, NHT and CABA with a good response to CABA. Results: Of these 70 pts, 52 received DOC-NHT-CABA, 15 DOC-CABA-NHT and 3 NHT-DOC-CABA. At rechallenge, 83% had a high-volume disease (CHAARTED definition), 10% had visceral mets, 66% consumed narcotic analgesics, 68 % were ECOG 0-1 and median neutrophil/lymphocyte ratio (NLR) was 3.1. CABA was rechallenged for a median of 6 cycles (25 mg/m2 q3w, 59%; 20 mg/m2, 27%; 16 mg/m2q3w 11%) with prophylactic G-CSF in 47%. Median time from last CABA cycle was 8.6 months (mo). CABA rechallenge had an acceptable tolerability: 7 pts (10%) had grade 3-4 toxicity (neutropenia). Data on efficacy are reported in Table 1. Median progression-free survival (PFS) was 11.3 mo with DOC, 12 mo with NHT, 11.9 mo with first CABA (median 8 cycles), and 7.8 mo with CABA rechallenge. Median OS calculated from the first life-extending therapy was 59.9 mo (95% CI 47.8; 66.4). Conclusions: This retrospective cohort of heavily treated mCRPC pts suggests that CABA rechallenge has a good activity with a manageable toxicity. CABA rechallenge might be an option in heavily treated pts still fit to receive chemotherapy. [Table: see text]

A randomized phase II trial of docetaxel plus carboplatin versus docetaxel in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial.

166 Background: Docetaxel is the standard first-line chemotherapy for patients with castration resistant prostate carcinoma (CRPC). Docetaxel re-challenge has never been tested in a prospective randomized clinical trial. As some studies supported the addition of carboplatin to docetaxel in this setting, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel monotherapy in docetaxel pre-treated CRPC patients. Methods: Patients with CRPC with a progression-free interval (PFI) of at least 3 months after initial treatment with docetaxel were randomized between docetaxel 75mg/m2 or docetaxel 60mg/m2 plus carboplatin AUC 4, both plus prednisone in a 3-weekly schedule. Treatment was continued until progressive disease, unacceptable toxicity or completion of 10 cycles. The primary endpoint is progression-free survival (PFS) (PSA and/or RECIST). Secondary objectives are overall survival, toxicity, PSA response and quality of life. Results: As a result of insufficient recruitment, the study was discontinued early after inclusion of 75 patients, instead of the targeted 150 patients. The median PFS was comparable between both groups (docetaxel 12.7 months versus combination therapy 11.7 months p = 0.99), and no difference in OS was found (median OS 18.5 months versus 18.9 months, p = 0.88). Rates of PSA response were comparable (response/stable PSA in 42.1%/39.4% of the patients in the monotherapy arm versus 35.1%/48.6% in the combination arm, NS). The incidence of grade 3-4 infections and gastro-intestinal (GI) side effects was higher in the docetaxel plus carboplatin arm (GI side effects 0% versus 13.9% p = 0.03; infection 2.7% versus 16.7% p = 0.056). The difference in febrile neutropenia (0% versus 11.1%) is not significant. Conclusions: For patients with CRPC and an initial good response to docetaxel, re-treatment with docetaxel monotherapy is a feasible, save and effective treatment. Addition of carboplatin resulted in more toxicity. Docetaxel re-challenge is a viable therapeutic option for selected patients. Clinical trial information: NTR3070.

P078 - Is there still a place for docetaxel rechallenge in metastatic castrate resistant prostate cancer?

P078 - Is there still a place for docetaxel rechallenge in metastatic castrate resistant prostate cancer?

Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation.

We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.

Is there still a place for docetaxel rechallenge in prostate cancer?

Three-weekly docetaxel plus prednisone is the standard first-line cytotoxic treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC). Today, several new treatment options are available for patients with tumor progression after first-line docetaxel: Abiraterone, enzalutamide, cabazitaxel, sipuleucel-T immunotherapy, and the radionuclide radium-223. However, despite the evolving scenario in CRPC treatment, the optimal sequencing of the innovative therapies remains unclear. The reintroduction of docetaxel at the occurrence of disease progression after a drug holiday (docetaxel rechallenge) was often proposed, and this chemotherapeutic agent showed to maintain antitumor activity in mCRPC patients. Docetaxel rechallenge may still constitute a valid treatment option mainly for patients with favorable response to first-line docetaxel, at least > 3 mo progression-free interval, age less than 75 years, good performance status, and acceptable docetaxel toxicity. The risk of cumulative toxicity must be evaluated, since sensory neuropathy, nail disorders and fatigue might occur on docetaxel rechallenge.

Bioclinical parameters driving decision-making of subsequent lines of treatment in metastatic castration-resistant prostate cancer.

Different options are available as second-line treatment of metastatic castrate-resistant prostate cancer: cabazitaxel, abiraterone, and enzalutamide. Phase III studies evaluating cabazitaxel and the two hormonal agents have been shown to significantly prolong overall survival compared to mitoxantrone and placebo, respectively. Several studies have also demonstrated feasibility and activity of docetaxel rechallenge in case of a sufficient progression-free interval (3–6 months), good performance status, and previous acceptable safety profile, thus providing an additional treatment option in clinical practice. Clinical and biological parameters should be considered to tailor II line treatment. In clinical practice, we can primarily evaluate patients' fitness according to age, performance status, symptomatic disease, comorbidities, and expected safety profile of each drug. Different prognostic/predictive factors may be considered, such as presence of bone-limited or visceral metastases, length of androgen deprivation therapy (ADT) before chemotherapy, time to progression after docetaxel, Gleason score, PSA doubling time, and serum testosterone, even if their clinical relevance is still debated. This review will discuss current options of innovative drugs sequencing and selection according to bioclinical parameters.

Rational indication for docetaxel rechallenge in metastatic castration‐resistant prostate cancer

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Docetaxel rechallenge has shown preserved anti-tumour activity and has therefore been proposed as an option for further treatment in patients with metastatic castration-resistant prostate cancer, who have shown a good response to first-line chemotherapy with docetaxel. The present study provides evidence of docetaxel activity in patients who were treated with full-dose (75 mg/m(2) ) 3-weekly docetaxel at first-line chemotherapy and rechallenge. It shows that PSA response to first-line chemotherapy may provide a rational indication for docetaxel rechallenge. • To determine whether prostate-specific antigen (PSA) response at first-line chemotherapy with docetaxel correlates with PSA response and survival at docetaxel rechallenge in patients with metastatic castration-resistant prostate cancer (mCRPC). • We retrospectively evaluated the oncological outcomes of patients with mCRPC, who were treated with full-dose (75 mg/m(2) ), 3-weekly docetaxel plus prednisone/prednisolone at first-line chemotherapy and rechallenge, between 1999 and 2011, at our institution. • The endpoints were PSA-progression-free survival (PSA-PFS) and overall survival (OS) at docetaxel rechallenge. • Statistical analyses included Kaplan-Meier curves and log-rank tests to evaluate the effect of PSA response at first-line chemotherapy on PSA-PFS and OS at rechallenge. • Fourty-four patients were included in the analysis. • At a median (range) follow-up of 26.4 (9.8-89.8) months after the first administration of docetaxel, 24 (55%) patients had died. At first-line chemotherapy, 36 (82%) patients achieved a reduction in PSA level of ≥50%. At rechallenge, 10 (28%) patients responded with a reduction of ≥50% for a second time. • The median (95% confidence interval [CI]) PSA-PFS was 5.9 (95% CI 3.5-6.8) months and the median OS was 21.8 (95% CI 19.9-23.7) months at docetaxel rechallenge. • Of the PSA response variables evaluated, only a PSA level reduction of ≥50% at first-line chemotherapy correlated significantly with prolonged PSA-PFS (5.8 vs. 4.5 months; P= 0.01) and OS (22.1 vs. 7.2 months; P= 0.03) at rechallenge. • In the present single-institution study, a reduction in PSA level of ≥50% at first-line chemotherapy with docetaxel correlated with superior PSA-PFS and OS in the rechallenge setting and might, therefore, present a rational indication for docetaxel rechallenge.

Survey on management of metastatic hormone-refractory prostate cancer upon progression during or following first-line chemotherapy in five European countries.

e15198 Background: In Europe, docetaxel is the standard first-line chemotherapy (1L) for patients with metastatic hormone-refractory prostate cancer (mHRPC). Upon progression, either during or after 1L chemotherapy, treatment options are limited. This study evaluated how patients who progressed during or after 1L docetaxel between Oct 2009 and Jun 2010 were managed. Methods: A representative sample of 349 physicians (oncologists, urologists) who managed patients with mHRPC selected from Germany, France, UK, Spain and Italy were surveyed. Information on the treatments used at the time of progression (during or within the first 6 months following 1L treatment with docetaxel was provided. Results: Information on a total of 2,870 mHRPC patients was provided of which 2,670 (94 %) had received docetaxel in 1L. 1,389 (52%) patients progressed during 1L docetaxel or within 6 months following treatment; of these, 615 (44 %) received as 2L chemotherapy (Table). Conclusions: In this study, mitoxantrone was the most commonly used chemotherapy agent for 2L treatment of patients with mHRPC who progressed during treatment or within the first 6 months following the end of 1L. Docetaxel rechallenge was uncommon for patients experiencing progression early, during or after the end of 1L. [Table: see text]

Patterns of second-line chemotherapy for metastatic prostate cancer in the United States.

e15193 Background: Patients with prostate cancer progressing from first-line (1L) docetaxel have limited approved treatment options available. Study is to evaluate patterns of second-line (2L) chemotherapy in a US managed care between 2004 and 2010. Methods: Patients with metastatic prostate cancer (mPC) and treated with docetaxel as 1L chemotherapy after July 1, 2004 were ascertained from the OptumInsight database. We evaluated type and timing of chemotherapy and relationships between patient characteristics, physician specialty, healthcare costs and geographic region, 6 months prior to 1L docetaxel and choice of 2L chemotherapy. Results: Patients (N=1,173) were on average 71 yrs old at onset of 1L docetaxel. During a mean follow-up period of 18 months, 38% of patients received 2L treatment. Out of the patients received 2L therapy, 32% received mitoxantrone (MITO), 24% with docetaxel rechallenge (RECH), 14% carboplatin (CARB), and 12% paclitaxel (PAC), plus 11% on Combo therapy. Examination of the 2L treatment groups showed that during the 6 months prior to 1L docetaxel, the RECH group (n=101) was older (73yrs), had fewer hospital admissions (12%), lower comorbidity burden [Charlson Comorbidity Index (CCI)=7.4], lower total healthcare costs ($10,083), and 78% seeing an oncologist; relative to MITO group (n=143) with 70 yrs, 16% hospital admissions, CCI of 7.5, total healthcare costs of $12,074, and 80% seeing an oncologist. The combo group (n=52) was 66 years old, with 19% hospital admissions, CCI of 8, total healthcare costs of $20,505, and 92% seeing an oncologist. Median time to MITO from the start of 1L docetaxel was 184 days, 309 days to RECH and 223 days to Combo therapy. Midwest (36%) and West (37%) were more frequently using MITO than Northeast (26%) and South (31%), while RECH was more frequently used in Northeast. Conclusions: Patients with mPC in US were most frequently treated with MITO or RECH as 2L chemotherapy after 1L docetaxel. MITO was also given sooner than RECH, hence a valid comparator for comparative effectiveness evaluation on new 2L therapy. Rechallenge with docetaxel increased with time and was given to patients with lower disease burden and healthcare costs than the MITO or Combo group.