This month, I will be covering some of the data from this year’s American Society of Clinical Oncology^® (ASCO) meeting. In this edition, I will review a number of the abstracts in melanoma, gynecologic oncology, genitourinary cancers, and breast cancers.

Presentations from the Genitourinary Cancers Session at The Annual Oncology Meeting

Prostate cancer presentations served as the majority of GU presentations during the 2009 ASCO meeting. I’m going to discuss 5 of those abstracts to be followed by 1 bladder cancer abstract and 3 renal cell abstracts.

Abstract 5009: Southwest Oncology Group S9921: Prolonged event-free survival in high-risk prostate cancer (PC) patients receiving adjuvant androgen deprivation.

Glode and colleagues presented the results of Southwest Oncology Group S9921 Trial Prolonged event-free survival in high-risk prostate cancer patients receiving adjuvant androgen deprivation. In this trial, 983 patients with prostate-specific antigen (PSA) >20, T3b, T4 or N1 or Gleason >8, or T3a, positive margin, and Gleason 7 were randomly assigned to receive combined androgen blockade (CAB) with goserelin plus bicalutamide for 2 years versus the same androgen deprivation therapy plus mitoxantrone and prednisone every 3 weeks x 6. Of the 496 patients randomized to the CAB arm, 376 completed 2 years of CAB per protocol. Of these, 189 had sufficient follow-up testosterone measurements which that were assessable for testosterone recovery. Among the 481 eligible CAB patients, the 5-year PFS is 92.5% and the 5-year OS estimate is 95.1%. Per protocol, testosterone levels were measured at 6-month intervals until recovery. After completion of the CAB, the median recovery time of testosterone was 9.5 months. The 6-month, 12-month, and 18-month overall testosterone recovery was 27.8%, 75.3%, and 89.5%, respectively. The conclusions of the authors were that SWOG 9921 shows better than predicted disease-free survival in high risk prostate cancer patients who received 2 years of complete androgen blockade. In addition, 75% of patients have testosterone recovery to above castrate level within 1 year of stopping CAB.

The remaining 4 prostate cancer abstracts revolve around the use of agents that target the androgen receptor (AR). Despite the fact that prostate cancers appear to become resistant to androgen blockade, in fact, the androgen receptors are overexpressed. Patients identified as castration resistant, have increased androgen receptor protein, AR mRNA overexpression, increased AR DNA copy number, and increased androgen synthesis.

Abstract 5011: Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer (CRPC).

Scher and colleagues presented the results of this trial. MDV3100 is a second-generation antiandrogen engineered for activity in prostate cancer cells that overexpress the AR. It binds the AR more potently than bicalutamide and inhibits nuclear translocation of the AR and its binding to DNA. It also induces apoptosis in prostate cancer cells. Patients with progressive CRPC were enrolled in sequential cohorts of 3 to 6 patients and increasing doses of MDV3100. Eventually, 140 patients were enrolled in the trial. Of note, there were 2 witnessed seizures at the upper dose levels. The MTD was determined to be 240 mg/day. Sixty patients were chemotherapy naïve, and their time to PSA progression has not yet been met. For those who have been exposed to chemotherapy, the time to PSA progression is 186 days. The >50% PSA decline was seen in 62% of the chemotherapy-naïve patients, and was 51% in those previously exposed to chemotherapy. The authors concluded that MDV3100 is active in CRPC both before and after chemotherapy and is generally well-tolerated. A phase III placebo-controlled survival trial in post-docetaxel CRPC patients is beginning this year.

Abiraterone inhibits CYP 17 that is an enzyme within the adrenal synthesis pathways. The enzyme is critical in both the androgen and cortisol pathways. Thus, to prevent the feedback increase in adrenocorticotropic hormone (ACTH) as a result of blocking cortisol production, prednisone is given with abiraterone in the clinical trials.

Abstract 5047: A multicenter phase II study of abiraterone acetate (AA) in docetaxel pretreated castration-resistant prostate cancer (CRPC) patients (pts).

Reid et al presented the results of this trial. Forty-seven patients with CRPC who had failed androgen deprivation therapy and had prior docetaxel chemotherapy received AA orally daily. Patients had a median of 3 prior hormonal therapies, including 6 who had received ketoconazole. Maximal PSA declines of >30%, >50%, and >90% were observed in 69%, 51%, and 15% of patients. Seventeen percent of patients had a PR, and 66% had stable disease by RECIST criteria. Median duration on treatment was 167 days. The authors noted that a phase III trial assessing the efficacy and safety of AA and prednisone in CRPC patients who have received docetaxel is underway.

Abstract 5048: Phase II multicenter study of abiraterone acetate (AA) plus prednisone therapy in docetaxel-treated castration-resistant prostate cancer (CRPC) patients (pts): Impact of prior ketoconazole (keto).

Danila et al reported results of this phase II trial. Of the 56 patients with available data, 24 had been previously exposed to ketoconazole. Forty-five percent of patients experienced a >50% decline in PSA (33% vs 53% for ketoconazole vs no prior ketoconazole). Eight percent of patients experienced a PR and 62% SD for those with measurable disease. The authors stated that ketoconazole-naïve patients will be selected for entry into the phase III trials.

Abstract 5049: Circulating tumor cells (CTC) in patients with metastatic castration-resistant prostate cancer (CRPC) receiving abiraterone acetate (AA) after failure of docetaxel-based chemotherapy.

Fleisher et al presented the results of a trial evaluating the significance of circulating tumor cells (CTC) in patients with metastatic CRPC receiving AA after failure of docetaxel-based chemotherapy. Forty-eight patients were treated with AA and the primary endpoint was a >50% decline in PSA from baseline. They monitored the changes in CTC number with therapy. Among patients with a baseline CTC >5, the CTC decline to <5 was associated with a decline in PSA by >50% (P<.001). The authors suggested that changes in CTC with treatment may represent a valuable intermediary endpoint for clinical benefit. Prospective testing of CTC’s is also being undertaken in the phase III trial as noted in the previous abstracts.

Abstract 5018: A multicenter phase II study of cisplatin (C), gemcitabine (G), and bevacizumab (B) as first-line chemotherapy for metastatic urothelial carcinoma (UC): Hoosier Oncology Group GU-0475.

Hahn et al from the Hoosier Oncology Group presented the results of this phase II study. Forty-five patients with metastatic or unresectable, chemo-naive urothelial cancer received cisplatin 70 mg/m² day 1, gemcitabine 1000-1250 mg/m² days 1 and 8, and bevacizumab 15 mg/kg day 1 on an every 21 day cycle. The primary statistical endpoint was PFS. Response rates, toxicity, and OS were secondary endpoints. Although the usual toxicity from bevacizumab including proteinuria and hypertension were observed, a larger than expected number of deep vein thrombosis (DVT) or pulmonary emboli (PE) were seen including 39% of patients receiving gemcitabine at 1250 mg/m², falling to 8% of the 25 patients who received 1000 mg/m². The authors made the following conclusions:

1. Bevacizumab adds significantly to the toxicity of the chemotherapy
2. The PFS was 8.2 months that did not meet the designed primary endpoint
3. The OS of 19.1 months is beyond that expected from cisplatin and gemcitabine alone.

The authors suggested that a phase III trial to further define the toxicity risk versus the clinical benefit of bevacizumab addition to platinum-based doublets is planned in this population.

With regards to renal cell carcinoma, 2 of the 3 trials investigated the use of bevacizumab in addition to interferon alfa, and 1 of the trials investigated the use of the multikinase antiangiogenesis inhibitor pazopanib.

Abstract LBA5019: Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival for CALGB 90206.

Rini et al presented the OS data for CALGB 90206, a phase III trial randomizing patients with confirmed metastatic RCC with a component of clear cell histology, and no prior systemic treatment to interferon-alfa 9 MU TIW, or the same dose of interferon plus bevacizumab 10 mg/kg every 2 weeks. The primary statistical endpoint was OS. The median PFS was 8.4 months for the combination arm, and 4.9 months for the interferon alone arm (P<.0001). Overall survival was improved by a non-significant 1-month interval favoring the combination arm. The authors speculated that survival was not able to be demonstrated because the majority of the patients went on to receive second-line therapy including other vascular endothelial growth factor (VEGF)–targeted therapies. The overall response rate was 13.1% in the interferon arm, and 25.5% in the combined arm.

Abstract 5020: Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-α2a (IFN) in metastatic renal cell carcinoma (mRCC).

Escudier, et al presented the final results this phase III trial. The AVOREN trial randomized 649 nephrectomized patients with advanced renal cell carcinoma to interferon alfa + placebo versus interferon alfa + bevacizumab. The primary statistical endpoint was OS, with multiple secondary endpoints. Prior publications had shown that PFS was increased from 5.4 months to 10.2 months with the addition of bevacizumab. As with the CALGB trial, there was a non-significant trend towards OS favoring the use of bevacizumab in this trial. These authors also concluded that the use of subsequent systemic therapy, especially the use of sunitinib, sorafenib, or another tyrosine kinase inhibitor, likely influenced the difficulty obtaining an improved survival.

Abstract 5021: A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC).

Sternberg, et al presented the results of this trial of pazopanib. Pazopanib is an oral multikinase angiogenesis inhibitor. In this trial, 435 patients with advanced RCC were randomized 2:1 to receive pazopanib versus placebo. Patients were given the option to receive pazopanib via an open-label study at progression. The median PFS for placebo was 4.2 months compared to 9.2 months for patients receiving pazopanib. Progression-free survival in the treatment-naïve subpopulation was even more striking with a median PFS of 2.8 months versus 11.1 months. Despite the fact that half the patients randomized to placebo eventually received pazopanib after progressive disease the median OS was improved from 18.7 months to 21.1 months (P = .02). The safety profile was typical for the oral multikinase angiogenesis inhibitors. This agent will continue to be investigated in the setting of metastatic renal cell carcinoma.

OncoFacts™ Editor:

Christy Russell, MD

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