Dr. Guru Sonpavde, MD (Clinical Assistant Professor, Baylor College of Medicine) reported about an open label, phase II trial of sunitinib (Sunitinib, marketed as Sutent, and previously known as SU11248 is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) on January 26, 2006. – Wikipedia) for men with metastatic CRPC (castration resistant prostate cancer) following prior docetaxel chemotherapy.
The subjects of the study were given 50 mg of oral Sunitinib daily for 4 of every 6-week cycle until progression and up to a maximum of 8 cycles. Progression was defined as the first occurrence of any of the following: two distinct new lesions on bone scan, progression of measurable disease by RECIST criteria, worsening of pain by 2 points on the six-point present pain intensity (PPI) scale, urinary tract obstruction, bone-related events or a deterioration of performance status to an ECOG score of 3-4. The researchers did not use PSA increases to determine progression. All the men participating in the trial had progressed following prior administration of docetaxel. Additionally, 36.2% of patients had received one other chemotherapeutic agent and 11.1% had also received prior bevacizumab (an FDA approved drug designed to inhibit the formation of new blood vessels to tumors.)
This phase II trial was very modest in size as only 36 men participated. The relatively high composite 12-week PFS (progression free survival) of 75.8% accompanied by 50% and 30% PSA declines in 12.1% and 21.2% of patients, support the possible use of sunitinib in treating well progressed CRPC.
Additionally, of 18 assessable patients, two (11.1%) exhibited an unconfirmed 30% tumor shrinkage by RECIST and eight (44.4%) exhibited some reduction in tumor size. In addition, two (2) of the four (4) men who had received prior bevacizumab displayed a 50% PSA decline and a 30% PSA decline, suggesting that these agents may not be completely cross-resistant. The phenomenon of PSA elevations coupled with clinical benefit (pain response) observed in other trials with similar TKIs (tyrosine kinase inhibitors) was also noted.
Although most toxic effects expierenced by the subjects were mild, the majority of the men (52.8%) discontinued therapy due to toxic effects. As a result, the median TTF (time to failure) was a more modest 11.8 weeks compared to the median PFS of 19.4 weeks. Fatigue, anemia, nausea, anorexia and neutropenia (failure of the bone marrow to make enough white blood cells) were the most common toxic effects experienced by the subjects.
Severe grade 3-4 toxic effects were infrequent with fatigue (n = 6), anorexia (n = 5), nausea (n = 3), and diarrhea and leukopenia (n = 2 each), being the most common. Two deaths were deemed to be possibly related to study therapy including one non-neutropenic infection and one cerebrovascular hemorrhage, although a definitive causative link could not be established. This elderly population of relatively heavily pretreated patients with metastatic CRPC may tolerate even mild toxic effects poorly compared with younger patients treated in other settings. Closer clinical monitoring and prompt dose reductions when early toxic effects were seen may have mitigated these events.
Given the high rate of discontinuation of therapy due to toxic effects, a lower dose and less heavily pretreated population may be more optimal (earlier use). There is an ongoing phase III trial in the second-line setting is comparing sunitinib 37.5 mg daily continuously plus prednisone versus placebo plus prednisone.
Joel T. Nowak MA, MSW