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Challenges remain regarding the mechanisms of docetaxel resistance, whether combination studies continue to make sense, and how the sequencing of docetaxel may impact toxicity and efficacy.
Daniel P. Petrylak, MD
Much progress has been made in the treatment of castration-resistant prostate cancer (CRPC) in recent years. New agents, such as sipuleucel-T, and in the second-line setting, abiraterone acetate, cabazitaxel, and enzalutamide, are now part of the treatment arsenal for this disease.
In addition, the novel alpha radiation-emitting agent radium-223 for patients with bone metastases from CRPC received FDA approval this year for both pre- and post-docetaxel patients. Daniel P. Petrylak, MD, discussed these and other developments at the 6th Annual Interdisciplinary Prostate Cancer Congress™ (IPCC®), where he served as co-chair. He is director of Genitourinary Oncology at the Yale Comprehensive Cancer Center in New Haven, Connecticut, and co-director of the center’s Signal Transduction Research Program.
Yet, despite the advent of these new agents, said Petrylak, “chemotherapy is still an important part of our management of prostate cancer,” and challenges remain regarding the mechanisms of docetaxel resistance, whether combination studies continue to make sense, and how the sequencing of docetaxel may impact toxicity and efficacy.
Docetaxel as first-line therapy in CRPC emanates from pivotal trials leading up to its approval by the FDA for CRPC in 2004,1,2 including the TAX 327 study confirming a clear survival benefit with administration every three weeks.3
“About 17% of patients treated with docetaxel and prednisone every three weeks were alive after three years, compared to about 12% of those who were treated with mitoxantrone,” noted Petrylak.
CRPC indicates castration-resistant prostate cancer.
Adapted from Petrylak DP. Advances in chemotherapy for castration resistant prostate cancer.
Presented at: 6th Annual Interdisciplinary Prostate Cancer Congress; March 16, 2013; New York, NY.
“That 5% difference is significant; nonetheless, we certainly want to do better than that,” he said.
Efforts to improve on the docetaxel-based regimen, he said, have understandably included targeting angiogenesis, in part because vascular endothelial growth factor (VEGF) is expressed in CRPC, and higher levels of VEGF correlate with poor outcomes. However, results of the multicenter, international, phase III VENICE trial reported earlier this year at the 2013 Genitourinary Cancers Symposium, comparing the addition of zivaflibercept to the docetaxel/prednisone regimen, versus docetaxel/prednisone and placebo in CRPC, did not lead to an improvement in survival. In addition, there was added toxicity and lower dose intensity in the experimental arm.4
Data that Petrylak presented at the 2012 European Society for Medical Oncology Meeting on the MAINSAIL trial,5 comparing the addition of lenalidomide versus placebo to the docetaxel regimen, again yielded “the same disappointing result,” he said. “In fact, it could be a little bit worse.” He noted that patients in the experimental arm had both lower overall survival (OS) and progression-free survival than those in the control arm, and adverse events such as neutropenia and febrile neutropenia resulted in less treatment exposure for patients receiving the combination therapy.
“Unfortunately, from these data, it is apparent that the single-agent angiogenesis approach combined with chemotherapy is not effective in this disease,” said Petrylak.Petrylak said that there also was good reason to expect that the addition of atrasentan, a selective endothelin receptor antagonist, to the docetaxel regimen might improve survival in CRPC, with the former targeting the bone and docetaxel targeting the tumor itself. However, a phase III trial (S0421) by the Southwest Oncology Group, comparing docetaxel plus placebo with docetaxel plus atrasentan in patients with hormone-refractory prostate cancer, again resulted in no difference in the control arm versus the experimental arm.
As to why this may have occurred, Petrylak suggested that more attention be focused on baseline biomarkers, for example, N-telopeptides, which are expressed in lung, breast, and prostate cancers.6,7 “We know that these particular bone markers correlate with a poorer overall prognosis.”
A subgroup analysis of patients in the S0421 trial receiving docetaxel with or without atrasentan found that patients with the highest bone marker levels received a significant survival benefit from atrasentan, despite their poorer prognosis.8 The significance of this finding, explained Petrylak, is that, “you’re targeting your drug against the bone where it makes the most sense to use it, and we have not been that smart in designing our clinical trials in the last couple of years.”
Similarly, he noted that the addition of dasatinib to standard therapy with docetaxel failed to improve survival in the READY trial, also reported at the 2013 Genitourinary Cancers Symposium.9
He said that investigators also have been looking at clusterin as a therapeutic target in CRPC. The protein is expressed in a variety of human cancers; in prostate cancer, its expression is increased in tumors with a higher Gleason score and with exposure to chemotherapy, radiation therapy, and hormone therapy, said Petrylak, thus conferring a “resistance advantage over other cells against chemotherapy, and certainly this may be one way that cells overcome chemotherapy exposure.”
The phase III SYNERGY study is currently evaluating first-line docetaxel, with and without custirsen (OGX- 011) in patients with metastatic CRPC, with a primary endpoint of OS. Custirsen blocks the production of clusterin, and phase II trial results suggest that the drug may provide an OS benefit and durable pain palliation for patients with prostate cancer.10 Results of the phase III SYNERGY trial are expected in late 2013.Cabazitaxel is approved by the FDA as second-line treatment after docetaxel. “The big difference with this drug is that it is active in multidrug-resistant cell lines whereas docetaxel is not,” said Petrylak. He noted that the results of the international, multicenter, phase III TROPIC trial, comparing cabazitaxel plus prednisone with mitoxantrone and prednisone, found an approximate three-month median OS advantage among patients receiving cabazitaxel.11
Petrylak said that adverse events associated with cabazitaxel included febrile neutropenia, which occurred in 7.5% of patients and accounted for five toxic deaths. He said such events may be addressed by providing prophylactic growth factors in the patient’s first cycle. “Generally, what I do is treat patients with prophylactic growth factors, and I also will start them at a lower dose,” he said. Petrylak mentioned that a randomized trial comparing 20 mg versus 25 mg of cabazitaxel is currently recruiting participants; the PROSELICA study (NCT01308580) aims to enroll 1200 patients.
He also noted that cabazitaxel is being evaluated as a frontline agent in comparison with docetaxel. In the ongoing phase III FIRSTANA trial, cabazitaxel plus prednisone is being evaluated versus docetaxel plus prednisone in an estimated 1170 patients with metastatic CRPC who have not been previously treated with chemotherapy.To date, no combination has been found to improve upon docetaxel plus prednisone, which remains the standard of care as first-line treatment for metastatic disease, said Petrylak, and he predicts that further manipulation of docetaxel-based chemotherapy is unlikely to provide therapeutic improvements.
However, markers for drug resistance are being identified. He and others are investigating patterns of cell division and differentiation, which play a role in chemotherapy resistance in CRPC. These studies also have revealed high levels of Hedgehog and Notch expression. “The best combinations that we’ve moved forth with have been docetaxel chemotherapy and both Hedgehog and Notch inhibition,” said Petrylak.
“I think this is where we have to start thinking about our markers,” he concluded, explaining that the focus must not only be on the clinical state of the disease, but also on how previous treatment affects the marker profile.
“The important thing is figuring out markers of resistance and progression in these patients, and I really think that is the way we will be able to develop new drugs rationally,” Petrylak said.