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Oncology Times:
doi: 10.1097/01.COT.0000414172.53819.a3
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The Shifting Landscape in Metastatic Castrate-Resistant Prostate Cancer

Tuma, Rabiya S. PHD

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SAN FRANCISCO—Treatment paradigms for patients with metastatic castrate-resistant prostate cancer (CRPC) are changing rapidly, with four new agents approved since 2010 and more likely to come. While everyone agrees that is good news, the questions now become how to optimize the agents in practice and how to select the right agent for the individual patient. To help with those issues, experts at the Genitourinary Cancers Symposium here reviewed pivotal data for the recently approved agents and provided a roadmap for agents in late-stage testing.

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4 Drugs, 4 Mechanisms

The recent spate of approvals breaks a six-year drought that followed docetaxel's approval in 2004. Three of the four new agents—abiraterone, cabozantinib, and sipuleucel-T—significantly prolong overall survival, while the fourth, denosumab, delays bone disease.

Overall survival data:

* Abiraterone + prednisone vs. placebo + prednisone: median overall survival of 14.8 months vs. 10.9 months for patients with disease progression on docetaxel; hazard ratio = 0.65, p < 0.0001

* Cabazitaxel + prednisone vs. mitoxantrone plus prednisone: median overall survival of 15.1 months vs. 12.7 months in patients with disease progression on docetaxel, hazard ratio = 0.7, p < 0.0001

* Sipuleucel-T vs. placebo: median overall survival of 25.8 months vs. 21.7 months; hazard ratio of 0.78, p = 0.03

“In a short time we have gone from one to four agents that improve overall survival,” said Gary MacVicar, MD, Assistant Professor in Hematology/Oncology at Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center in Chicago. “I think equally remarkable, in regards to overall survival, is that each of these agents is incorporating a different mechanism of action, arguably all new.”

Abiraterone is a Cyp17 inhibitor that blocks the synthesis of testosterone and cortisol. Despite the fact that existing androgen-deprivation therapies drive down the level of testosterone to castration levels, CRPC is still driven by the androgen receptor, meaning that further reduction in testosterone synthesis may slow the disease.

In general, the drug is well tolerated, but some patients do develop fluid retention, hypertension, and hypokalemia, so physicians need to monitor patients taking abiraterone, he said.

Cabozantinib is a tubulin-binding cytotoxic agent, “which at face value perhaps doesn't seem so interesting,” he said. However, even in early trials, the drug showed activity in men with CRPC whose disease had progressed on docetaxel.

Toxicity was an issue in the phase III cabozantinib trial, with increased febrile neutropenia, and diarrhea and potentially higher treatment-related mortality. Because of those adverse events, an ongoing trial is comparing a 20 mg/m2 dose with the 25 mg/m2 dose used in the registration trial.

“While [the toxicities] may temper our enthusiasm for chemotherapy agents after docetaxel, I still think there is room for use of the agent,” MacVicar said. “We just have to reserve it for use in patients with good performance, who can tolerate further chemotherapy. We need to be vigilant in monitoring our patients, and personally, I offer GM-CSF for higher-risk patients.”

Sipuleucel-T is an active cellular immunotherapy that is prepared individually for each patient. He said that although the treatment is thought to induce a T-cell response against the cancer, he remains unconvinced. “I would argue that the exact mechanism of action is unknown,” he said.

GARY MACVICAR, MD: W...
GARY MACVICAR, MD: W...
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Moreover because sipuleucel-T treatment does not show an effect on either PSA or progression-free survival, it is difficult for physicians to know how well a patient is responding or when to start alternative therapies. “Personally I consider this early in the course of mCRPC, mainly for those who would meet the phase III entry criteria,” MacVicar said. “If I have a patient who has symptoms or who has rapidly progressing disease, this is likely not the right choice.”

Finally, he discussed denosumab, an antibody that binds RANK ligand, blocking the signal from reaching the osteoclasts. The drug breaks a vicious cycle in which prostate cancer cells induce osteoblasts to produce RANK ligand; the RANK ligand triggers osteoclasts to resorb bone and release growth factors; the growth factors then stimulate tumor cell growth, which initiates the cycle all over again.

In the phase III registration trial, patients treated with denosumab had a median of 20.7 months until their first skeletal-related event compared with 17.1 months in patients treated with denosumab, which translated into an 18% relative risk reduction (p = 0.0002 for non-inferiority and 0.008 for superiority).

There was however, no difference in time to progression or overall survival between the two arms. Osteonecrosis of the jaw was equally common in the denosumab and zoledronic acid arms of the study (2% and 1%, respectively, p = 0.09), which means that physicians need to continue to monitor patients for this serious complication. Additionally hypocalcemia occurred in twice as many patients treated with denosumab as with zoledronic acid (13% vs. 6%, p < 0.0001). Therefore, patients on denosumab should receive calcium supplementation, according to MacVicar.

Adding to the mix of recently approved agents, he noted that investigators presented positive phase III trial data for MDV3100 at the meeting, which may lead to its regulatory approval (OT: “Major Survival Bump Predicted in Castrate-Resistant Prostate Cancer Patients; Two Agents Prolong Survival in Phase III Trials”). MacVicar also pointed out several ongoing phase III trials that oncologists should “keep on our dashboard for results in the near future” (see box on previous page).

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New Agents in Clinical Trials

Also at the meeting, Evan Yu, MD, Associate Professor at the University of Washington and Fred Hutchinson Cancer Research Center, described experimental agents currently in phase III randomized trials.

Five anti-angiogenesis agents are being tested in CPRC. Three trials have already turned up negative, showing that bevacizumab, lenalidomide, and sunitinib do not prolong overall survival. Meanwhile, a 1,200-patient trial testing the addition of aflibercept to docetaxel and prednisone has completed accrual and results are expected in the middle of this year.

Accrual is continuing for a 1,200-patient trial that compares tasquinimod versus placebo in patients with minimal or no symptoms and who have not yet received docetaxel.

Last year, cabozantinib, a dual MET and VEGF receptor inhibitor, made a splash when researchers showed complete or partial resolution of bone metastases in 82 out of 108 patients (75%) treated with the drug in a randomized discontinuation trial. “I think this is shocking,” Yu said, noting that physicians often see bone flares on scans with other agents, which is the opposite of what was seen with cabozantinib. There is evidence of bone turnover, however. Additionally a post-hoc analysis suggested a reduction in narcotic use for bone in patients on the trial.

With those data in mind, investigators have now launched two prospective randomized trials. One aims to measure the drug's impact on pain, whereas the other is designed to look at the drug's impact on overall survival. Both trials are in patients who have disease progression on docetaxel. Interestingly, both trials use a substantially lower dose of the drug than was used in the randomized discontinuation trial (60 vs. 100 mg daily) because of significant adverse events observed in that earlier trial.

EVAN YU, MD, agreed ...
EVAN YU, MD, agreed ...
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Yu also noted that results should be reported soon from an ongoing 1,500-patient trial that compares docetaxel with and without dasatinib. Microarray data indicated that Src expression is negatively correlated with androgen receptor activity in samples from patients with local and metastatic CRPC. A phase I/II trial with 46 patients suggested the drug combination is active, with 57% of patients showing a durable PSA decline of 50% or more and 60% of patients had partial responses by RECIST criteria, and 30% had disappearance of a lesion on a bone scan. Adverse events were not insignificant however, with 28% of patients having a grade 3 or 4 toxicity.

Finally, he described a second-generation antisense compound, OGX-011, that targets the anti-apoptotic Clusterin gene. The gene is upregulated after androgen-deprivation therapy and is highly expressed in higher Gleason grade tumors. In a neoadjuvant phase I trial, researchers showed a dose-dependent increase in the amount of drug that entered the tumor, in the level of mRNA and protein expression, and in the amount of apoptosis in the tumor.

“I love this phase I trial,” he said. “This was a very nice pharmacodynamic, pharmacokinetic study—again, very impressive.”

Initial results from a randomized phase II study were disappointing with no effect detected in progression-free survival when OGX-011 was added to docetaxel compared with docetaxel alone. However, a subsequent analysis a couple of years later suggested the drug had improved overall survival. Therefore investigators launched a randomized phase III trial in Europe and North America comparing the two regimens in 800 patients with metastatic CRPC; the primary endpoint is overall survival.

As final thoughts, Yu echoed what MacVicar had emphasized at the beginning of the session: It is critical that the newly approved agents have distinct mechanisms of action. “We should continue to look for new, “druggable' targets.”

Dr. MacVicar has served an advisory role for or received honoraria from Centocor Ortho Biotech, Novartis, Dendreon, and Sanofi-Aventis, and has received research funding from Medivation and Millennium. Dr. Yu received research funding from Bristol-Myers Squibb and Oncogenex.

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Ongoing Phase III Trials for Patients with Metastatic Castrate-Resistant Prostate Cancer
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Hormonal agents:

* Abiraterone + prednisone vs. placebo + prednisone in chemotherapy-naïve patients; primary endpoints: overall and progression-free survival

* Orteronel (TAK-700) + prednisone vs. placebo + prednisone in chemotherapy-naïve patients; primary endpoints: overall and progression-free survival.

* Orteronel + prednisone vs. placebo + prednisone in patients with disease progression on docetaxel; primary endpoint: overall survival.

* MDV3100 vs. placebo in chemotherapy-naïve patients; primary endpoints: overall and progression-free survival

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Immunotherapies:

* PROSTVAC, a PSA-encoding poxviral vaccine, with and without GM-CSF vs. placebo in chemotherapy-naïve patients; primary endpoint: overall survival

* Ipilimumab, an anti-CTLA-4 antibody, vs. placebo in chemotherapy-naïve patients; primary endpoint: overall survival

* Ipilimumab vs. placebo in patients with previous disease progression on docetaxel; primary endpoint: overall survival

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Meeting Cosponsors

The symposium is co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

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© 2012 Lippincott Williams & Wilkins, Inc.

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