Castration-Resistant Prostate Cancer: A Conversation With Cora N. Sternberg, MD

Cora N. Sternberg, MD

Physicians and patients with castration-resistant prostate cancer (CRPC) have an increasing number of treatment options that improve outcomes. Ten years ago, there were few choices for drug treatment, but now there are at least 6 effective medications, and more are in development. OBTN interviewed genitourinary cancer expert Cora N. Sternberg, MD, about treatment options for CRPC during the European Multidisciplinary Cancer Congress. Sternberg is chief of the Department of Medical Oncology at the San Camillo and Forlanini Hospitals in Rome, Italy.

OBTN: When did drugs emerge for treating CRPC?

Dr Sternberg: Before 2004, we had very little for these patients and the outlook was rather dismal. That year saw the approval of zoledronic acid and docetaxel. Now in 2011 we have sipuleucel-T, cabazitaxel, denosumab, and abiraterone.

What are some challenges in developing new drugs for CRPC?

Most patients with CRPC will develop bone metastases. Disease in the bone makes prostate cancer difficult to measure, as it is extremely challenging to evaluate bone metastases. We look at skeletal-related events (SREs), pathological fracture, need for radiation to the bone, surgery for the bone, and spinal cord compression to determine the best treatment option for the patient.

What endpoints are accepted in studies of new drugs for CRPC?

Overall survival [OS] is the most widely accepted endpoint for regulatory approval of a novel agent. We are lacking surrogate markers, but the Prostate Cancer Working Group 2 has developed some criteria that help international communication—we can use these criteria to measure disease progression in a congruent way. As a result of the criteria, we also no longer take patients off of a drug treatment based only on a rising PSA [prostate-specific antigen] level. One new potential surrogate marker is circulating tumor cells [CTCs]. CTC levels <5 appear to signal improved survival. This marker needs further validation, but is increasingly being incorporated into clinical trials. Nonetheless, we still desperately require a better understanding of the inter-patient molecular heterogeneity in prostate tumors (eg, ETS gene-rearrangements, PTEN-loss cancers, RAF rearrangements, CRCA carrier cancers).

Which was the first drug to show a difference in OS?

TAX-327 was the first large trial to demonstrate improved OS in CRPC, and this was a randomized trial comparing docetaxel versus mitoxantrone in 2004. The combination of docetaxel plus prednisone given every 3 weeks improved OS by 21% versus mitoxantrone plus prednisone. Docetaxel plus prednisone is now considered standard first-line chemotherapy. We want to improve upon these results, but thus far combinations of docetaxel with other agents such as bevacizumab have not been successful in improving OS. Ongoing trials include the combination of docetaxel with afibercept, lenalidomide, OGX-011, dasatinib, atrasentan, and zibotentan. Until recently, we also have not had proven results with second-line therapy.

Are there good second-line therapy choices now?

The TROPIC trial included 755 men with metastatic CRPC who progressed on first-line docetaxel plus prednisone. Second-line therapy with cabazitaxel plus prednisone improved OS by 30% versus mitoxantrone plus prednisone—an absolute difference of 2.4 months favoring cabazitaxel. Mitoxantrone plus prednisone was used as the control arm, because it has become the de facto second-line therapy, and a placebo arm was less acceptable to many patients. TROPIC participants had a median survival of 15.1 months. However, the combination of cabazitaxel plus prednisone carries formidable hematologic toxicity, with grade 3/4 neutropenia occurring in 80% of patients. It is possible that a lower dose of cabazitaxel (ie, 20 mg/m2, not 25 mg/m2 as used in the trial) would incur less toxicity. I use cabazitaxel with growth factor support, but this was not done in TROPIC.

What about treatment with bisphosphonates?

More recently, therapies targeting the bone have become a focus of CRPC treatment. About 80% to 90% of our patients have bone metastasis, and survival is poor if patients develop SREs. Zoledronic acid was found to decrease SREs versus placebo in metastatic CRPC, and since then, this bisphosphonate has become the standard of care for metastatic CRPC patients with bone disease.

A randomized, double-blind trial just published in The Lancet compared a monoclonal antibody against RANK ligand, denosumab, versus zoledronic acid in 1904 men with metastatic CRPC. Denosumab was superior to zoledronic acid, achieving an 18% risk reduction in SREs and an 18% reduction in the risk of a second SRE at least 21 days later.

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About 80% to 90% of our patients have bone metastasis, and survival is poor if patients develop SREs. Zoledronic acid was found to decrease SREs versus placebo in metastatic CRPC, and since then, this bisphosphonate has become the standard of care for metastatic CRPC patients with bone disease. ”

—Cora N. Sternberg, MD

Are there any advantages/disadvantages of zoledronic acid versus denosumab?

Denosumab is given by monthly subcutaneous injection and does not require renal monitoring, as does zoledronic acid. The rate of osteonecrosis of the jaw is, however, equivalent with denosumab and zoledronic acid. Good dental hygiene prior to therapy is required for both agents.

In your presentation, you mentioned cabozantinib. Are there any recent data on that drug?

Cabozantinib is a dual inhibitor of the VEGF receptor and MET. A randomized discontinuation phase II trial design was used to evaluate cabozantinib. The randomization of stable patients to cabozantinib or placebo was stopped early because of the dramatic results observed. At 12 weeks, cabozantinib achieved a 74% regression of soft-tissue lesions, 19% complete remission (CR) of bone metastases, and 56% partial remission (PR) of bone metastasis. Many patients got out of bed and started walking again. This drug will be evaluated in a larger study and the endpoint will be pain improvement, and a second study will evaluate OS.

At this meeting, there was a lot of excitement about a new radiopharmaceutical called radium-223 (Alpharadin). What are your thoughts about this agent?

Radium-223 is an alpha particle emitter that acts as a calcium mimic and naturally targets the bone. This drug induces double-strand DNA breaks in adjacent tumor cells and has a very short penetration with minimal damage to surrounding normal tissues. At this meeting, preliminary results of ALSYMPCA were released and were very exciting. The study enrolled 922 patients with CRPC and at least 2 bone metastases and randomized them to radium-223 or placebo. Planned follow-up is 3 years. Radium-223 achieved a hazard ratio of 0.695, which translates into a 30% improvement in OS and a 39% improvement in SREs. This is the first demonstration of improved survival with a radiopharmaceutical, and it is the first drug targeted to bone metastases in prostate cancer that has been shown to improve OS. Other drugs targeted to the bone treat symptoms. We will be hearing a lot more about this interesting nontoxic drug. In this trial, there were more side effects reported in placebo patients than in those randomized to radium-223.

We’ve also heard a lot about immunotherapy in prostate cancer. Where is that approach positioned now?

The IMPACT trial found that the sipuleucel-T vaccine achieved a median OS benefit of 4.1 months versus placebo. That study included CRPC patients who were minimally symptomatic; approximately 15% received previous chemotherapy. Patients were randomized 2:1 to the vaccine given every 2 weeks for 3 injections versus placebo.

When should chemotherapy be initiated for patients with CRPC?

Patients usually prefer to delay chemotherapy. Physicians use chemotherapy in patients with rapidly progressing disease who are symptomatic, those with visceral disease, and those with a rapid PSA doubling time.

Where do some newer agents fit in the treatment algorithm for CRPC?

Under study is the possible role for the following agents prior to the initiation of docetaxel: abiraterone, MDV3100, sipuleucel-T, TAK-700, PROSTVAC, zibotentan, and tasquinimod. Following docetaxel, there is now a role for abiraterone, cabazitaxel, and radium-223. In addition, MDV3100, TAK-700, ipilimumab, and cabozantinib are all of great interest.

What are some present challenges regarding optimizing treatment for CRPC?

It is an exciting time for physicians treating patients with CRPC. We have to remember that prostate cancer is not just a single disease; it has a great deal of heterogeneity. We have many new and not-so-new therapies, but we still have to determine what is the best drug for which patient and the best sequencing. We hope that better molecular characterization of tumors and international collaboration can tease out the answers to these important questions.

Alice Goodman is a medical writer in New York City.