Satraplatin in the treatment of hormone-refractory prostate cancer

Authors


Cora N. Sternberg, Department of Medical Oncology, San Camillo and Forlanini Hospitals, Nuovi Padiglioni, Circonvallazione Gianicolense 87, 00152 Rome, Italy.
e-mail: cstern@mclink.it

Abbreviations
HRPC

hormone-refractory prostate cancer

ECOG

Eastern Cooperative Oncology Group

PS

performance status

EORTC

European Organization for Research and Treatment of Cancer

TTP

time to progression.

INTRODUCTION

Prostate cancer is most common malignancy among men in the USA, and the incidence of this disease has been increasing. It is estimated that ≈ 232 000 new cases will be diagnosed in 2005, with >30 000 deaths projected [1]. Most men diagnosed with localized prostate cancer are treated with curative radiation therapy or surgery. For those in whom such treatment is unsuccessful or who present with metastatic disease, androgen-deprivation therapy is often used to improve disease-free and overall survival. However, most of these patients subsequently develop hormone-refractory prostate cancer (HRPC) and require other forms of treatment such as chemotherapy. Recent findings from two phase III trials (TAX 327 and South West Oncology Group 9916) showed for the first time that docetaxel-based chemotherapy can prolong survival in patients with HRPC (overall survival 18–19 months) [2,3]. However, the benefit of such treatment is limited (median time to PSA progression 6–8 months), with many patients progressing after taxane-based therapy [4]. Second-line therapy options are limited and include chemotherapeutics, e.g. mitoxantrone and estramustine, and novel agents undergoing clinical evaluation, like those targeting signal transduction pathways and apoptosis [5,6]. There is therefore a significant need for the treatment of patients with HRPC in both the first- and second-line settings.

SATRAPLATIN

Satraplatin [bis-(acetato)-ammine dichloro-(cyclohexylamine) platinum IV; formerly known as JM-216] is a third-generation orally available platinum analogue that shares some structural similarities with cisplatin but also has important differences. Satraplatin is more lipophilic than cisplatin and, unlike cisplatin, carboplatin and oxaliplatin, satraplatin is orally bioavailable. Like other platinum analogues, satraplatin appears to act by binding to DNA and forming intra- and interstrand crosslinks, resulting in cell-cycle arrest in the G2 phase and eventual apoptosis. Evidence suggests that while satraplatin DNA-adducts are efficiently repaired by the nucleotide-excision repair pathway, they are not recognized by the DNA mismatch repair system that acts on cisplatin and carboplatin adducts [7].

Satraplatin has potent growth inhibition on several human cancers both in vitro and in small-animal models. In small cell lung cancer cell lines, satraplatin has a 50% inhibitory concentration in the submicromolar range, equivalent to or less than that of cisplatin [8]. The cytotoxic activity and cell-line specificity of satraplatin was also comparable to that of cisplatin when evaluated against three other platinum analogues (cisplatin, carboplatin and tetraplatin) in several ovarian cancer cell lines [9] and against human ovarian cancer xenografts in mice [7]. Satraplatin inhibited the growth of cervical cancer cell lines, including those resistant to cisplatin [10]. Furthermore, satraplatin had additive or synergistic activity when combined with other anticancer methods. For example, the combination of satraplatin and oral etoposide was synergistic in a P388 murine leukaemia model, and growth inhibition of H460 human lung cancer xenografts was at least additive when satraplatin was combined with radiation [11,12]. Micromolar concentrations of satraplatin were also cytotoxic for androgen-sensitive and androgen-insensitive human prostate carcinoma cell lines, providing in part the basis for its clinical development in this tumour type [13]. These preclinical results indicate that satraplatin has antitumour activity comparable to that of cisplatin in several different tumour types, and suggest that satraplatin may have potential for use in combined regimens with other commonly used cancer therapeutics or with radiation therapy.

PHARMACOKINETICS

Satraplatin is rapidly absorbed after administration, reaching peak plasma levels within 2 h. At a dose of 100 mg/m2, on day 5 the half-life of satraplatin was relatively prolonged, at ≈ 12 h [14,15]. Satraplatin and its metabolites are largely bound to blood components and plasma proteins; consequently, little drug appears as free platinum in the plasma ultrafiltrate. Pharmacokinetic studies showed that when satraplatin is administered at doses up to 150 mg/m2 daily using a 5-day schedule, there was a linear correlation between plasma ultrafiltrate area under the curve and dose [14,15]. At higher doses (e.g. single doses >200 mg/m2 per day) the pharmacokinetics are not linear due to saturable absorption of satraplatin from the gut. There was also a correlation between systemic satraplatin exposure, as measured by ultrafiltrate on days 1 and 5, and the level of thrombocytopenia [14]. In small-animal tumour models the 5-day schedule was associated with optimal pharmacokinetics, antitumour activity and tolerability [16].

Phase I trials of single-agent satraplatin have explored several different dosing schedules, from daily dosing to every 3 weeks [14–19]. These studies confirmed that the recommended dose and schedule in chemo-naive patients is 80–120 mg/m2/day for five consecutive days, repeated every 4–5 weeks.

To date, >600 patients have participated in satraplatin clinical trials; the dose-limiting toxicity is myelosuppression (primarily neutropenia and thrombocytopenia), which is dose-dependent and reversible [15]. Other adverse effects of satraplatin are similar to those seen with carboplatin. While satraplatin can cause emesis (grade 3/4 in 13% of courses), that can be successfully managed by premedication with serotonin antagonists such as ondansetron and granisetron. Treatment with satraplatin has not resulted in nephrotoxicity, ototoxicity or neurotoxicity, which are often seen with other marketed platinum agents such as cisplatin. Because satraplatin is orally administered, infusion-related adverse events are eliminated, and therapy can be administered on an outpatient basis.

SATRAPLATIN IN PROSTATE CANCER

On the basis of preclinical activity in human HRPC cell lines and the efficacy in this tumour type in phase I trials, satraplatin has been evaluated for treating HRPC. Five phase II or phase III trials of satraplatin in prostate cancer have been initiated or are ongoing (Table 1). Three of these studies were terminated before achieving the planned accrual by the pharmaceutical sponsor at the time (Bristol-Myers Squibb) because they decided not develop this drug further. Thus, only preliminary data are available for these trials. Peereboom et al.[20] reported on a completed multicentre phase II trial of satraplatin in 39 chemo-naive patients with progressive HRPC. Patients were treated with satraplatin 120 mg/m2 daily for 5 days every 28 days, with prophylactic oral odansetron; 22 were evaluable for response. Of the nine patients with measurable disease, one with measurable liver lesions had a partial response and six had stable disease. There were reductions in PSA level by more than half in seven patients (32%) for >28 days, and six (27%) had PSA level decreases of >80%. Toxicity was considered to be manageable. Grade 3/4 haematological toxicities consisted of neutropenia (grade 3, eight patients), including one with febrile neutropenia; thrombocytopenia (grade 3, 10 patients; grade 4, five), and anaemia (grade 3, five). Grade 3/4 nonhaematological toxicities included transient increases in aspartate transaminase (grade 3, three patients) and bilirubin (grade 4, two), diarrhoea (grade 3, five; grade 4, three), nausea (grade 3, two; grade 4, one) and vomiting (grade 3, one; grade 4, one). These authors concluded that satraplatin is an active drug against HRPC, with manageable toxicity.

Table 1. 
Phase II and III trials of satraplatin in prostate cancer
Investigator/trialDescriptionRegimenNo. of patients
  1. P, prednisolone; S, satraplatin.

EORTC 30972Phase III trial of S + P vs P for first-line treatment of HRPCS: 100 mg/m2/day × 5 days, for 5 weeks50
P: 10 mg twice daily 
CA142-029Phase III trial of S + P vs P for symptomatic HRPCS: 100 mg/m2/day, × 5 days, for 5 weeks14
P: 10 mg twice daily 
Peereboom et al.[20]Multicentre phase II trial for first-line treatment of HRPCS: 120 mg/m2/day × 5 days, for 4 weeks39
CA142-026Multicentre phase II trial of S + P for second- line treatment of HRPCS: 80–100 mg/m2/day × 5 days, for 3 weeks10
P: 10 mg twice daily 
SPARCPhase III trial of S + P vs P for second-line treatment of HRPCS: 80 mg/m2/day × 5 days, for 5 weeksongoing
P: 5 mg twice daily 

These encouraging results and indications of activity in prostate cancer in the other phase II studies led the European Organization for Research and Treatment of Cancer (EORTC) to initiate a phase III trial of satraplatin plus prednisolone vs prednisolone alone for the first-line treatment of patients with HRPC [21]. Patients were randomized to treatment with either satraplatin 100 mg/m2 daily on days 1–5 every 5 weeks, plus prednisolone 10 mg twice daily for 35 days, or to prednisolone alone at the same dose and schedule. The target accrual was 380 patients, but only 50 were enrolled when the study was terminated early by the sponsoring company. The results of this trial showed that the combination of satraplatin and prednisolone resulted in a statistically significant increase in PSA response compared to the prednisolone-alone arm (33% vs 9%; P = 0.046; Table 2) [22]. The median progression-free survival was also significantly greater for the satraplatin/prednisolone combination (5.2 vs 2.5 months; P = 0.023), with a hazard ratio of 0.50 (Fig. 1). While overall survival was not statistically different, probably because there were too few patients, the median survival in the satraplatin arm was nearly 15 months compared with ≈ 12 months for the prednisolone arm (14.9 months vs 11.9 months; P = 0.579).

Table 2. 
The PSA response in the EORTC 30972 phase III trial
VariablePrednisoloneSatraplatin + prednisolone
N2327
n (%):
Response 2 (9) 9 (33)
Stable disease 3 (13) 5 (19)
Progression17 (74)12 (44)
Not evaluable 1 (4) 1 (4)
Figure 1.


Progression-free survival (A) and overall survival (B) from the EORTC 30972 phase III trial of satraplatin/prednisolone (green line) vs prednisolone alone (red line) in HRPC. The median (95% CI) progression-free survival was significantly greater for the satraplatin arm than the prednisolone arm, at 5.2 (2.8–13.7) vs 2.5 (2.1–4.7) months (P = 0.023) and numerically greater for overall survival, at 14.9 (13.7–28.4) vs 11.9 (8.4–23.1) months (P = 0.579). The hazard ratio was 0.84 (0.46–1.55).

Toxicity was generally low with the satraplatin/prednisolone combination. Serious haematological toxicities in the satraplatin arm included neutropenia (26%, grade 3), thrombocytopenia (30%, grade 3), and absolute neutrophil count (15%, grade 3/4). Serious nonhaematological toxicities (all grade 3) consisted of diarrhoea, vomiting, infection, cardiovascular and hyperglycaemia (all 7.4%). Grade 3/4 alkaline phosphatase elevation (11%) was also noted in this group of patients. In the combined arm, six patients (22%) required a reduced satraplatin dose due to haematological toxicity and nine (33%) had a dose delay related to toxicity; four (15%) discontinued therapy with satraplatin due to toxicity or refusal. The median satraplatin dose intensity was the planned dose of 100 mg/m2 per day.

These encouraging results suggested that combined satraplatin and prednisolone was feasible and active as a first-line treatment for patients with HRPC. The statistically significant increase in progression-free survival and the numerical increase in overall survival, coupled with an acceptable toxicity profile, supported further investigation of this regimen in a larger, more highly powered phase III trial.

THE SPARC PHASE III TRIAL

On the basis of the results of the EORTC study and previous phase II data indicating that satraplatin was associated with significant activity in HRPC, a phase III trial was initiated in 2003 to extend these results and determine the overall survival benefit. This study, known as SPARC (‘satraplatin and prednisolone against refractory cancer’), is a multicentre, multinational double-blind, placebo-controlled trial designed to compare satraplatin plus prednisolone to prednisolone alone for the second-line treatment of HRPC. The trial is powered to detect a 30% increase in time to progression (TTP) with ≥ 85% power (637 events).

In the SPARC trial, patients with metastatic HRPC in whom one previous cytotoxic chemotherapy regimen has failed are randomized to either satraplatin plus prednisolone or placebo plus prednisolone, in a 2 : 1 ratio in favour of the satraplatin arm (Fig. 2). Satraplatin (80 mg/m2) or placebo will be administered twice daily on days 1–5 of a 35-day cycle, and prednisolone 5 mg will be given twice daily on days 1–35. Patients randomized to the satraplatin arm also receive oral granisetron (1 mg) as an anti-emetic, twice daily on days 1–5, whereas those on the prednisolone-only arm will take an anti-emetic placebo.

Figure 2.


The scheme for the phase III SPARC trial of satraplatin plus prednisolone vs placebo plus prednisolone as second-line therapy for HRPC. Patients randomized to the satraplatin arm also receive oral anti-emetic therapy on days 1–35, whereas those on the prednisolone-only arm receive an anti-emetic placebo.

Key inclusion criteria for this trial are: metastatic prostate cancer with disease progression after one line of therapy with a chemotherapy regimen; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2; life expectancy >3 months; previous medical or surgical castration (i.e. hormone-refractory); and adequate bone marrow, hepatic and renal function (Table 3). Primary exclusion criteria include more than one previous treatment with a chemotherapy regimen or previous treatment with a platinum analogue; previous diagnosis with another malignancy; significant previous radiation or radionuclide therapy; inability to adequately absorb satraplatin after oral administration (e.g. patients with major gastrointestinal surgery or any gastrointestinal disease affecting absorption); a contraindication for steroid therapy; and the presence of brain metastases. All patients must give written informed consent.

Table 3. 
The SPARC phase III trial of satraplatin plus prednisolone in HRPC: key study criteria
Inclusion criteriaExclusion criteria
Stage D2 metastatic prostate cancerMore than one previous chemotherapy
Progression after one previous chemotherapy regimenPrevious platinum-containing compounds
ECOG PS ≤ 2Previous malignancy
Life expectancy >3 monthsPrevious significant radiation or radionuclide therapy
Surgical or medical castration (hormone-refractory)Major gastrointestinal surgery or disease affecting absorption
Adequate bone marrow, hepatic and renal functionContraindication to steroid therapy
Brain metastases

The primary endpoint of the SPARC trial is the TTP of disease, defined as the time from randomization to first report of disease progression. The TTP is a composite measurement based on the first occurrence of either tumour progression, a skeletal event, or symptomatic disease progression. Tumour progression is based on the Response Evaluation Criteria in Solid Tumors criteria for soft-tissue lesions or the occurrence of two or more new lesions on bone scan. A skeletal event includes a bone fracture, the need for bone surgery or radiation, or initiation of bisphosphonate therapy. Patients with symptomatic progression experience an increase in the patient-assessed Present Pain Index score, an increase in the consumption of analgesics, weight loss ≥ 10%, or a decline in ECOG PS. The secondary trial endpoints are overall survival and TTP for pain. Target accrual for this trial, which involves 137 active clinical trial sites worldwide, is 912 patients.

DISCUSSION

Preliminary clinical trial data suggest that satraplatin is active in patients with HRPC. In the EORTC trial, treatment with satraplatin/prednisolone resulted in a statistically significantly greater progression-free survival and PSA response than prednisolone alone in chemo-naive patients with HRPC. Satraplatin toxicities appear to be similar to those with carboplatin, and satraplatin lacks the nephrotoxicity, ototoxicity and neurotoxicity often caused by cisplatin. Additional larger trials with sufficient statistical power could support these promising results with satraplatin in the first-line setting. Satraplatin could thus have a role in the long-term control of HRPC, prolonging survival and reducing treatment-related mortality.

New, effective treatments are also needed for second-line therapy of HRPC for those patients who progress on taxane-based first-line chemotherapy. Final results of the SPARC trial are therefore anxiously awaited to show the activity of satraplatin plus prednisolone as second-line therapy and its impact on TTP, time to pain progression, and overall survival.

CONFLICT OF INTEREST

None declared.

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