Novel Concepts Include New Agents, Combinations

Oliver Sartor, MD

Oncology specialists who treat patients with metastatic castration-resistant prostate cancer (mCRPC) can look forward to choosing from an expanding array of therapeutic tools, including regimens that couple immunotherapy with novel agents and radiation, according to Oliver Sartor, MD.

During his presentation at IPCC, Sartor noted that patients with prostate cancer likely will require multiple drugs to achieve cure rates, just as “it takes four drugs to cure Hodgkin disease, one of our most curable malignancies.”

“I think we’re all looking forward to the day when we can start to combine these agents,” said Sartor, who is medical director and a professor in the Department of Medicine, Section of Hematology & Medical Oncology at the Tulane Cancer Center in New Orleans, Louisiana.

As it stands now, Sartor said there have been six phase III trials either completed in recent years or with interim results in which a survival advantage has been demonstrated in mCRPC (Table).

Novel therapeutics also are in development. Sartor reviewed agents involving these four concepts: immunotherapy, with ipilimumab (Yervoy; Bristol- Myers Squibb) and PROSTVAC-VF-TRICOM (Bavarian Nordic); the targeted alpha-emitter, radium-223 (Alpharadin; Bayer HealthCare); an inhibitor of c-MET and vascular endothelial growth factor receptor 2 (VEGFR-2), cabozantinib (formerly XL184; Exelixis); and the RANK ligand inhibitor and bone-strengthening agent denosumab (Xgeva; Amgen).

Table. Phase III Trials in Metastatic CRPC With a Survival Advantage

Trial

Design

HR

Survivala (months)

Differences

TAX 327 N = 1006

Docetaxel/prednisone vs mitoxantrone/prednisone

0.76

18.9 vs 16.5

2.4 months

IMPACT N = 512

Sipuleucel-T vs control cells

0.78

25.8 vs 21.7

4.1 months

TROPIC N = 755

Cabazitaxel/prednisone vs mitoxantrone/prednisone

0.70

15.1 vs 12.7

2.4 months

COU-301 N = 1195

Abiraterone/prednisone vs placebo/prednisone

0.65

14.8 vs 10.9

3.9 months

ALSYMPCA N = 922

Radium-223 + best standard of care (BSC) vs placebo/BSC

0.70

14.9 vs 11.3^b

3.6 months

AFFIRM N = 1199

MDV3100 vs placebo

0.63

18.4 vs 13.6

4.8 months

^aSurvival outcomes are not directly comparable because the trials varied on whether docetaxel was administered. Participants in the TAX 327, TROPIC, COU-301, and AFFIRM trials received docetaxel, while most participants in the IMPACT trial did not. Participants in ALSYMPCA either were treated with docetaxel, not a candidate for docetaxel, or received patient's/physician's choice.

^b Represents updated data not yet presented.

Sartor O. Immunomodulatory and bone targeted therapeutics in metastatic castrate-resistant prostate cancer. Presented at: 5th Annual Interdisciplinary Prostate Cancer Congress (IPCC); March 31, 2012; New York, NY.

Immunotherapies

In the area of immunomodulatory therapies in prostate cancer, Sartor said he is “particularly excited” about the prospects for ipilimumab and the PROSTVAC-VF-TRICOM vaccine.

Ipilimumab, which is approved for the treatment of advanced melanoma, is being explored in prostate cancer as monotherapy with and without radiation and/or chemotherapy, and in separate trials in combination with PROSTVAC-VF-TRICOM and GM-CSF.

(PROSTVAC is a sequentially dosed combination of two poxviruses, Vaccinia and Fowlpox, each encoded with PSA plus TRICOM [three costimulatory molecules, B7.1, ICAM-1, and Lfa-3]). The first poxvirus is Vaccinia-PSA-TRICOM; the second is Fowlpox-PSA-TRICOM. GM-CSF, granulocytemacrophage colony stimulating factor, helps activate white blood cells).¹

While some patients have experienced dramatic responses on ipilimumab combinations, there may be serious toxicities, such as the grade 3/4 adverse events as diarrhea, rashes, and panhypophysitis found at higher doses in combination ipilimumab and PROSTVAC-VF-TRICOM trials.²

“One of the things you have to be cautious about is that when you give this particular antibody— ipilimumab—you take the brakes off the immune system and have the capacity to get a variety of autoimmune-type responses,” Sartor said.

PROSTVAC-VF-TRICOM, an off-the-shelf vaccine that uses a triad of costimulatory molecules mixed with viruses to enhance T-cell activation, has shown improvement in median overall survival (OS) versus placebo (25.1 months vs 16.6 months, respectively) but not progression-free survival (3.8 months vs 3.7 months, respectively) in a phase II trial.³ The vaccine is now undergoing evaluation in a large, global, placebo-controlled phase III study involving patients with minimally symptomatic mCRPC.

Bone-Targeted Agents and Inhibitors

With radium-223, researchers are examining a new concept in which the injected alpha particle targets osteoblastic bone metastases and kills genetically heterogeneous cancer cells. “That’s a dramatic and important observation, and it gives some confidence that the alpha particle is going to have a real role to play in the future,” said Sartor, who is a leading investigator into radium-223.

Interim results from the ALSYMPCA trial demonstrated an improvement in OS for patients who received radium-223 versus placebo (14.0 months vs 11.2 months, respectively).⁴ The agent also delivered an improvement in the median time to first skeletalrelated event versus placebo (13.6 months vs 8.4 months, respectively),⁵ with a favorable adverse-event profile. Bayer HealthCare is pursuing a new drug application with the FDA under the agency’s Fast Track program.

In the area of dual inhibition, cabozantinib has shown the ability to inhibit angiogenesis (VEGFR-2) and the c-MET pathway, interfering with the “fight or flight” response of tumors, said Sartor. Although cabozantinib was able to induce substantial antitumor activity in many of the patients who enrolled in a phase II trial but it “is not for the faint of heart,” said Sartor, noting that it has resulted in grade 3 fatigue and loss of appetite.⁶ Notably, he said, the FDA did not approve a special protocol assessment for a planned pain palliation trial, a designation that would have enabled the drug to be evaluated under an expedited review. A phase III trial is planned.

Another inhibitor, denosumab, interferes with osteoblast production and has been approved by the FDA for the prevention of skeletal-related events in patients with bone metastases from solid tumors. However, the agency’s Oncologic Drugs Advisory Committee did not support expanding denosumab’s indications to CRPC after a phase III trial in which patients experienced a median 4.2-month advantage in progression-free survival versus placebo but a higher rate of osteonecrosis of the jaw.⁷ Sartor said he agreed with the panel’s decision.

Novel Combinations

In addition to studies of novel therapeutics administered as monotherapy, researchers also are exploring combinations. Sartor, for example, is planning a clinical trial that would evaluate the therapeutic anticancer vaccine sipuleucel-T (Provenge; Dendreon) with radium-223.

“There’s a good rationale for putting these two agents together,” Sartor explained in an interview. “Radium-223 will help release tumor antigens that will make the cancer more immunologically accessible, if you will, and the idea of adding in the sipuleucel-T to radium makes good sense. We’ll be testing this in a prospective trial.”

Yet, although clinicians are excited about the expanding armamentarium, Sartor added a cautionary note about mounting cost concerns for patients, insurers, and the healthcare system.

“Clearly, multiple drugs will be necessary to cure mCRPC, and that is our greatest challenge today,” said Sartor, adding that some patients are struggling with their copayments now. “How are we going to afford it all? We’re really reaching a point in our society where we’re going to have to come to some terms and balance the benefits of new drug development against the cost of medicine and come out with something in between.”

References

1. PROSTVAC specifications. Bavarian Nordic website. http://www.bavarian-nordic.com. Accessed April 24, 2012.
2. Madan RA, Mohebtash M, Arlen PM, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial [published online ahead of print February 10, 2012]. Lancet Oncol. 2012;13(5):501-508. doi:10.1016/S1470-2045(12)70006-2.
3. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer [published online ahead of print January 25, 2010]. J Clin Oncol. 2010;28(7):1099-1105.
4. Parker C, Heinrich D, O’Sullivan JM, et al. Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alphapharmaceutical: results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. J Clin Oncol. 2012;30 (suppl 5; abstr 8).
5. Sartor AO, Heinrich D, Helle SI, et al. Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases: a phase III randomized trial (ALSYMPCA). J Clin Oncol. 2012;30 (suppl 5; abstr 9).
6. Hussain M, Smith MR, Sweeney C, et al. Cabozantinib (XL184) in metastatic castration resistant prostate cancer (mCRPC): results from a phase 2 randomized discontinuation trial. Poster presented at: 2011 ASCO Annual Meeting; June 3-7, 2011; Chicago, Il. Abstract 4516. Published at: http://www.exelixis.com/cabozantinib/clinicaltrial-information/prostate-cancer. Accessed April 23, 2012.
7. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasisfree survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial [published online ahead of print November 15, 2011]. Lancet. 2012;379(9810):39-46.