Nab-Paclitaxel Continues to Be Explored in Advanced Urothelial Cancer

Srikala Sridhar, MD, MSc, FRCPC

The rapid growth in available therapies for genitourinary cancers has not extended to urothelial cancer. “Unlike prostate cancer and kidney cancer, in which there has been a remarkable number of new drugs approved, urothelial cancer has largely lagged behind in terms of drug development,” according to Srikala Sridhar, MD, MSc, FRCPC. At the 2012 Chemotherapy Foundation Symposium, Sridhar discussed how nab-paclitaxel might offer some hope for patients with advanced urothelial cancer.

Cisplatin-based combination regimens are the current standard of care for patients developing or presenting with metastatic urothelial disease; however, despite high response rates with these treatments, the median survival time is only 12 to 14 months.

There are no standard second-line treatments for urothelial cancer. In single-agent trials in this setting, the median survival time has been 5 to 10 months (Table). “Second-line urothelial cancer remains a major unmet medical need,” said Sridhar, medical oncologist, Princess Margaret Hospital, head of GU Medical Oncology Site Group, and assistant professor of Medicine, University of Toronto, Canada.

Taxanes, and specifically paclitaxel, have been the most commonly used drugs in the second-line setting, according to Sridhar. Although taxanes are well tolerated, “They require steroid premedication to prevent hypersensitivity, mostly due to the solvent cremaphor in which the taxanes are dissolved,” said Sridhar. Nab-paclitaxel, an albumin-bound nanoparticle formulation of paclitaxel, is solvent-free and thus does not require steroid premedication. Another advantage with nab-paclitaxel is that its infusion times are shorter. Based on the lack of treatment options and the established tolerability of nab-paclitaxel, Sridhar led a trial that examined the drug as a secondary treatment for urothelial cancer (ASCO GU 2011; Abstract 241).

Sridhar et al’s phase II trial involved 48 patients (median age, 66 years) with metastatic urothelial carcinoma who had progressed during or after first-line cisplatin-based chemotherapy. Prior taxane treatment was not allowed. Eighty-three percent of patients were male, 83% had an ECOG performance status of 0 to 1, 73% had visceral/bone metastases, and 53% had prior platinum response.

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Dr. Srikala Sridhar on Nab-Paclitaxel in Urothelial Cancer

Patients received 260 mg/m² of nab-paclitaxel intravenously every 3 weeks. The median number of cycles administered was six. Dose reductions were required in 33% of patients, but were primarily due to fatigue or neuropathy.

In 47 evaluable patients, the rates of partial response and stable disease were 32% and 21%, respectively. Forty-seven percent of patients had progressive disease. Median progression-free survival (PFS) was 6 months, and median overall survival (OS) was 10.8 months. As shown in the Table, the nab-paclitaxel efficacy data compare well with other single agents tested in the second-line setting.

Table. Single-Agent Second-Line Trials in Advanced Urothelial Cancer

Trial

Regimen

Phase

N

Response Rate

TTP (Months)

Median Survival

Lorusso 1998

Gemcitabine

II

35

23%

3.8

5

Albers 2002

Gemcitabine

II

30

11%

4.9

8.7

Vaughn 2002

Paclitaxel

II

31

10%

2.2

7.2

Pronzato 1997

Ifosfamide

II

20

5%

NR

NR

Witte 1997

Ifosfamide

II

56

20%

2.5

5.5

McCaffrey 1997

Docetaxel

II

20

13%

NR

9

Sweeney 2006

Pemotrexed

II

47

28%

2.9

9.6

Dreicer 2007

Epothilone B

II

45

12%

2.7*

8

Bellmunt 2009

Vinflunine

III

370

9%

3.0*

6.9

Sridhar 2011

nab-Paclitaxel

III

47

32%

6.0*

10.8

*Progression-free survival. TTP indicates time to progression.

The drug also had an acceptable toxicity profile. “Overall, we did feel that [nab-paclitaxel] was fairly well tolerated,” said Sridhar. The most common grade 3/4 toxicities were pain (23%), fatigue (10%), weakness (8%), neuropathy (6%), dyspnea (6%), and hypertension (6%).

Sridhar et al concluded that the positive results of their phase II study warranted further exploration of nab-paclitaxel in second-line urothelial cancer. At the Chemotherapy Foundation Symposium, Sridhar was excited to report that this additional research is now in development.

The National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) is initiating a multicenter randomized trial comparing nab-paclitaxel to paclitaxel in patients with advanced urothelial cancer progressing on or after a platinum-containing regimen. The study is designed to accrue 220 patients and randomize them 1:1 to either 260 mg/m² of nab-paclitaxel or 175 mg/m² of paclitaxel intravenously every 3 weeks.

The primary objectives of the study include PFS, OS, objective response rate, and safety and tolerability. The trial will also examine quality of life, attempt to identify biomarkers for efficacy and toxicity, determine whether genetic variation affects drug response, and conduct a cost analysis of nab-paclitaxel versus paclitaxel from a government payer perspective. The NCIC-CTG is hoping to open the trial in spring 2013.

In her concluding remarks, Sridhar said that she is optimistic about progress in treating urothelial cancer because there is now a “recognition that advanced urothelial cancer is a field that needs a strong collaborative effort, not just among researchers, clinicians, investigators, patients, caregivers, and families, but also among our industry partners and the FDA.”