New Clues to Optimizing mCRPC Regimens

Combination therapies may help mCRPC patients with bone metastases.
Combination therapies may help mCRPC patients with bone metastases.

AMSTERDAM—Studies presented at the 2013 European Cancer Congress may provide insight into how patients with metastatic castration-resistant prostate cancer (mCRPC) respond to various sequences or combinations of recently approved therapies.

For example, researchers from the U.S. reported promising results of a phase 2 trial in which mCRPC patients were co-administered sipuleucel-T—an immunotherapy approved for use in asymptomatic or minimally symptomatic mCRPC patients—with concurrent or sequential abiraterone acetate plus prednisone. The results suggest that sipuleucel-T can be successfully manufactured during concurrent abiraterone acetate plus prednisone treatment without affecting product potency and immunologic prime-boost responses.

“These preliminary data are encouraging, and suggest that combining sipuleucel-T and abiraterone acetate plus prednisone is possible,” said lead investigator Eric J. Small, MD, Professor of Medicine and Chief of the Division of Hematology and Oncology at the University of California San Francisco (UCSF). “It is not known if the potential for an immunostimulatory effect from low testosterone levels achieved with abiraterone may be offset by the potentially immunosuppressive effects of prednisone.”

Dr. Small, who is Deputy Director of the UCSF Helen Diller Family Comprehensive Cancer Center, also noted that the study demonstrated that the co-administration of sipuleucel-T with abiraterone acetate and prednisone was generally well tolerated, and did not affect the product characteristics of sipuleucel-T or its capacity to show an immune response.

Cabazitaxel vs. abiraterone

Other studies presented at the conference suggest that cabazitaxel may offer advantages over abiraterone acetate for second-line treatment in mCRPC patients whose disease has progressed while on docetaxel. In a study of 113 post-docetaxel patients, Guru Sonpavde, MD, Director of Urologic Oncology at the University of Alabama in Birmingham, and colleagues at the US Oncology Network found that cabazitaxel followed by abiraterone acetate (DCA) is associated with better outcomes than abiraterone acetate followed by cabazitaxel (DAC) even after controlling for clinical prognostic factors. The median overall survival was 18.2 months among the 77 men in the DCA group compared with 11.8 months among the 36 men in the DAC group. The median time to treatment failure (from the start of second-line therapy post-docetaxel to the end of second-line therapy) was 5.2 months in the DCA group versus 4.3 months in the DAC group. The median duration of cabazitaxel treatment was significant longer in the DCA than the DAC group (195 vs. 89), with 22% of patients in the DCA group receiving less than three months of cabazitaxel compared with 64% of those in the DAC group. The median duration of abiraterone acetate treatment was similar in both groups: 126 days in the DCA group and 123 days in the DAC group.

As for why fewer patients received cabazitaxel after abiraterone acetate rather than the reverse, Dr. Sonpavde told Renal & Urology News, “Our hypothesis is that this may be due to poorer performance status later in the disease course that render patients ineligible to receive chemotherapy or renders them suboptimal for a longer course of chemotherapy. In contrast, abiraterone is more tolerable and may be more feasible later in the disease course even with poorer performance status.”

In light of study findings, Dr. Sonpavde said, clinicians should at least consider tailoring therapy. “Perhaps those with good performance status after docetaxel should have a discussion about cabazitaxel as well as abiraterone and make a decision after considering these data,” he said.

In a separate study of 129 mCRPC patients who progressed on docetaxel, Michel D. Wissing, MSc, of Leiden University Medical Center in Leiden, the Netherlands, and colleagues found that DCA was associated with an overall survival rate similar to that of DAC. The patients treated with DCA, however, had significantly better biochemical progression-free survival (9.2 vs. 7.4 months). The 129 patients included 61 patients who received DCA and 68 who received DAC.

“There seems to be no advantage for giving abiraterone before cabazitaxel when giving both agents,” Wissing told Renal & Urology News. “Overall survival did not differ significantly, time to PSA progression was better in patients receiving cabazitaxel before abiraterone than vice versa, and there was a similar trend for PFS.”

If a physician plans to give a patient both cabazitaxel and abiraterone, Wissing said, he would recommend giving cabazitaxel first, based on his team's findings. If the patient has experienced heavy toxicity from docetaxel or is in relatively poor physical condition, it may be better to start with abiraterone.

Both agents had a decreased antitumor effect as third-line treatment, but Wissing noted that “there were still some partial responses in patients, so patients should still receive such third-line therapy if they are eligible.” Some research suggests the presence of cross-resistance between docetaxel and abiraterone. “Our study results suggest the same may be true for cabazitaxel and abiraterone.” He added, however, that their study does not give a definite answer because other factors could have biased findings. For example, patients were probably in worse condition at this stage of their disease. Nevertheless, another study also presented at the conference demonstrated cabazitaxel resistance in abiraterone-resistant cell lines, he noted.

Enzalutamide plus abiraterone

Also at the conference, Eleni Efstathiou, MD, of M.D. Anderson Cancer Center in Houston, and colleagues presented findings of a study demonstrating that a combination of enzalutamide and abiraterone acetate achieves steeper declines in PSA levels in men with mCRPC compared with either drug alone. Results showed that 72% of patients achieved a 50% of greater decrease in PSA, 48% achieved a 90% or greater decrease, and 10% achieved undetectable levels.

By comparison, phase 3 trial results showed that 54% of patients treated with enzalutamide (N Engl J Med 2012;367:1187-1197) and 29% of those treated with abiraterone (N Engl J Med 2011;364:1995-2005) achieved a 50% of greater decline in PSA. Recent findings suggest that such PSA declines are associated with improved outcomes. At the 2013 American Society of Clinical Oncology annual meeting, Charles J. Ryan, MD, and colleagues presented results of a study of abiraterone treatment in chemotherapy-naïve mCRPC patients showing that declines in PSA correlate with improved radiographic progression-free survival. Compared with men who had no PSA decline, those with a PSA decline less than 50% had a 25% decreased risk of radiographic progression and those with a decline of 90% or greater had a 78% decreased risk.

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