Activity of second‐line chemotherapy in docetaxel‐refractory hormone‐refractory prostate cancer patients

Rosenberg, Jonathan E.; Weinberg, Vivian; Kelly, Wm. Kevin; Michaelson, M. Dror; Hussain, Maha; Wilding, George; Gross, Mitchell E.; Hutcheon, Douglass; Small, Eric J.

doi:10.1002/cncr.22811

Cited by 169 publications

(81 citation statements)

References 28 publications

(35 reference statements)

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“…[11][12][13][14][15] For now, mitoxantrone is considered the de facto second-line chemotherapy, but has limited activity and increased toxicity in this setting.…”

Section: Second-line Systemic Chemotherapymentioning

confidence: 99%

Guidelines for the management of castrate-resistant prostate cancer

Saad¹,

Hotte²

2010

CUAJ

119

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DefinitionCastrate-resistant prostate cancer (CRPC) is defined by disease progression despite androgen depletion therapy (ADT) and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of preexisting disease, and/or the appearance of new metastases.Advanced prostate cancer has been known under a number of names over the years, including hormone-resistant prostate cancer (HRPC) and androgen-insensitive prostate cancer (AIPC). Most recently, the terms CRPC or castration recurrent prostate cancer were introduced with the realization that intracrine/paracrine androgen production plays is significant in the resistant of prostate cancer cells to testosterone suppression therapy. 1 In their second publication, the Prostate Cancer Working Group (PCWG2) defined CRPC as a continuum on the basis of whether metastases are detectable (clinically or by imaging) and whether the serum testosterone is in the castrate range by a surgical orchidectomy or medical therapy. 2 This continuum creates a clinical-states model where patients can be classified. The rising PSA states (castrate and noncastrate) signify that no detectable (measurable or non-measurable) disease has ever been found. The clinical metastases states (castrate and noncastrate) signify that disease was detectable at some point in the past, regardless of whether it is detectable now.Prognosis is associated with several factors, including performance status, presence of bone pain, extent of disease on bone scan and serum alkaline phosphatase levels. Bone metastases will occur in 90% of men with CRPC and can produce significant morbidity, including pain, pathologic fractures, spinal cord compression and bone marrow failure. Paraneoplastic effects are also common, including anemia, weight loss, fatigue, hypercoagulability and increased susceptibility to infection.CRPC presents a spectrum of disease ranging from patients without metastases or symptoms with rising PSA levels despite ADT, to patients with metastases and significant debilitation due to cancer symptoms.

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“…[11][12][13][14][15] For now, mitoxantrone is considered the de facto second-line chemotherapy, but has limited activity and increased toxicity in this setting.…”

Section: Second-line Systemic Chemotherapymentioning

confidence: 99%

Guidelines for the management of castrate-resistant prostate cancer

Saad¹,

Hotte²

2010

CUAJ

119

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“…Mitoxantrone with prednisone is the only other cytotoxic regimen indicated for CRPC based on a palliative benefit (improvement in the McGill-Melzack bone pain score) rather than a prolongation of OS [6,7]. PSA response, as defined above, occurs in approximately 20%-30% of patients treated with mitoxantrone in the first-line setting [1,2,6,7] and in 15% of patients treated in the second-line setting following docetaxel [8,9]. Taken together, these data suggest only modest activity for mitoxantrone as a first-or second-line agent for CRPC treatment.…”

Section: Docetaxel-resistant Crpcmentioning

confidence: 99%

“…The dose-limiting toxicity (DLT) was fatigue with the weekly schedule, whereas neutropenia and mucositis were dose limiting with the 3-weekly dosing schedule; peripheral neuropathy was also a significant toxicity. Ixabepilone was evaluated in a series of early-phase studies in patients with CRPC (summarized in Table 1) [9,[43][44][45][46][47][48][49][50], with promising antitumor activity as monotherapy and in combination with mitoxantrone and prednisone in men who have progressed on docetaxel. Furthermore, antitumor activity with ixabepilone has been observed in the first-line and docetaxel-resistant settings.…”

Section: Clinical Experience With Epothilones In Crpc Ixabepilonementioning

confidence: 99%

“…Furthermore, of the patients with bone metastases at baseline, 24 of 40 (60%) in the single-agent ixabepilone arm and 28 of 36 (78%) in the combination arm had stable or improved disease on bone scan for Ն3 months. In a retrospective analysis of patients who went on to receive second-line taxane therapy, 51% achieved a Ն50% PSA decline [9]. Responses were reported both in patients who had achieved a first-line response with ixabepilone (61%) and in those who had not (33%), indicating that there is incomplete crossresistance between these two classes of drug.…”

Section: Chemotherapy-naïve Crpc Patientsmentioning

confidence: 99%

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The Epothilones: New Therapeutic Agents for Castration-Resistant Prostate Cancer

Dorff

Gross

2011

The Oncologist

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The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostatespecific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first-and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC. The Oncologist 2011;16:1349 -1358

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“…2 Mitoxantrone with prednisone, which has been demonstrated to improve quality of life as front-line therapy, has been used extensively, with 50% PSA declines reported in 20% of patients previously treated with docetaxel. [3][4][5] Ixabepilone, an epothilone analog, has similarly been demonstrated to have a 17% response rate in this setting. Of interest, objective responses to mitoxantrone/prednisone after second-line ixabepilone and conversely to ixabepilone after second-line mitoxantrone/prednisone were observed during a randomized phase 2 study, suggesting there is noncross-resistance with the 2 regimens.…”

mentioning

confidence: 96%

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Harzstark

Rosenberg

Weinberg

et al. 2010

Cancer

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BACKGROUND: Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncrossresistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination. METHODS: Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m 2 and mitoxantrone 12 mg/m 2 administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity. RESULTS: Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed !50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed !30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively. CONCLUSIONS: These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;117:2419-25.

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Activity of second‐line chemotherapy in docetaxel‐refractory hormone‐refractory prostate cancer patients

Cited by 169 publications

References 28 publications

Guidelines for the management of castrate-resistant prostate cancer

Guidelines for the management of castrate-resistant prostate cancer

The Epothilones: New Therapeutic Agents for Castration-Resistant Prostate Cancer

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

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