ASCO: Role of Chemotherapy and Novel Targeted Agents in Prostate Cancer

Daniel P. Petrylak, MD

As part of our coverage of the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 30–June 3 in Chicago, we are speaking with Daniel Petrylak, MD, professor of medical oncology and urology and the co-director of the signal transduction research program at Yale Cancer Center in New Haven, Connecticut. Dr. Petrylak will be presenting a perspective on the role of chemotherapy in prostate cancer at an Education Session at the meeting on Tuesday, June 3. Today we are discussing the role of chemotherapy in prostate cancer, as well as study results on novel targeted approaches and agents in development for prostate cancer that will be presented at the meeting.

  -Interviewed by Anna Azvolinsky  

Cancer Network: The treatment landscape for advanced prostate cancer has changed quite a bit over the last several years, with novel targeted agents approved as therapies, providing an improvement in treatment for patients beyond chemotherapy. Can you briefly discuss the agents that are now available to treat patients?

Dr. Petrylak: Basically, the agents fall into four different classes-immune therapies, hormonal agents, cytotoxic agents, and DNA-damaging agents. Sipuleucel-T was approved in 2010 for the treatment of patients with minimally symptomatic or asymptomatic castration-resistant prostate cancer. It is generally a treatment used early in the course of disease, particularly when patients are asymptomatic. It shows about a 4-month improvement in survival, but unfortunately, it does not show any difference in the time to progression or prostate-specific antigen (PSA) decline, and that may be related to its mechanism of action, being an immune therapy.

Hormonal agents that have been approved include enzalutamide and abiraterone. Abiraterone was the first-in-class agent that targeted the C17,20-lyase pathway, and it causes reduction in testosterone levels in tumor tissue. It has shown a survival benefit in postchemotherapy patients and shows improvement in progression-free survival in prechemotherapy patients. Enzalutamide is approved for postchemotherapy patients and shows about a 5-month improvement in survival. While it does show a survival benefit in prechemotherapy patients, the US Food and Drug Administration (FDA) approval for this indication is still pending at this point.

The cytotoxic agents docetaxel and cabazitaxel are both approved by the FDA. Docetaxel is generally used for those patients who are symptomatic or have visceral metastases. Cabazitaxel is approved for patients who have previously been treated with docetaxel. And then finally, in the DNA-damaging class, we have radium-223, which is approved for both pre- and postchemotherapy, and shows about a 3.5-month improvement in median overall survival in all patients who are treated. It is generally approved for those patients who have castration-resistant prostate cancer with symptoms.

Cancer Network: In the context of this newer treatment landscape, what is the current role of chemotherapy, in your view?

Dr. Petrylak: Chemotherapy does play a role. I think that the role is going to change with this year’s ASCO meeting. Traditionally, we have used chemotherapy for those patients who have metastases or visceral metastases, and who are symptomatic. And chemotherapy has been pushed down the line after some of these novel agents like abiraterone and enzalutamide. The question really is, is chemotherapy less effective in this particular situation? There may be a common mechanism with enzalutamide and abiraterone-mainly that docetaxel has been known to interfere with androgen receptor translocation, and that may explain why response rates are a little bit lower in some trials and retrospective analyses in those patients who have been on prior abiraterone. So, I think that those issues are important to determine, but generally, at least in this pre-ASCO time, chemotherapy is reserved for those patients who are castration-resistant.

Christopher Sweeney is presenting data at ASCO 2014 that evaluates 6 cycles of docetaxel, without prednisone, combined with hormonal therapy vs hormonal therapy alone in newly diagnosed metastatic patients. He demonstrated a survival benefit in favor of the earlier docetaxel, and from the press release, there is about a 20% improvement in the 3-year survival, particularly in those patients who have extensive metastases-in other words, visceral disease and more than 10 bone metastases. I strongly believe that you will see chemotherapy moved up front for select patients with castrate-sensitive prostate cancer, particularly those who have extensive disease.

Cancer Network: What are some of the other prostate cancer results you are looking forward to at this year’s ASCO meeting?

Dr. Petrylak: Well, there are different novel agents that are being evaluated. We are presenting data looking at the anti-prostate specific membrane antigen (PSMA) antibody in castration-resistant prostate cancer, and we are showing activity in those patients who have failed docetaxel and particularly those who have high expression of PSMA in their circulating tumor cells, as well as low neuroendocrine markers. This antibody is a cytotoxic agent complex or ADC. There are other PSMA antibodies also being evaluated, in addition to the one we are presenting on. There are other trials out there looking at novel agents that will come out in the next few years. Unfortunately, the antisense agent, custirsen, when combined with docetaxel showed no improvement in survival compared with docetaxel alone.

We will also be seeing data at this year’s ASCO meeting on TAK-700, which is a C17,20-lyase inhibitor, similar to abiraterone, but it does not have the same hydroxylase activity that lends itself to being administered without steroids, unlike abiraterone. Unfortunately, the prechemotherapy study that was performed with TAK-700 (TAK-700 plus prednisone vs prednisone alone) is not going to show a survival advantage but did show an improvement in progression-free survival. Those are the interesting presentations that will be at this year’s ASCO meeting.

Cancer Network: Do you expect any of these or any others to have immediate implications for how patients are treated in the clinic?

Dr. Petrylak: Right now we are awaiting some phase III trials, and I think these have implications as far as biology and drug design are concerned, but there are no phase III trials that have matured at this point, except the docetaxel in combination with hormonal therapy trial, which I do think has immediate implications for patient care. We will now be offering chemotherapy earlier, upfront, to patients when they first go on hormonal therapy if they have metastatic disease.

Cancer Network: What are some of these phase III trials that are ongoing in prostate cancer?

Dr. Petrylak: The ones that are ongoing include the Exelixis studies looking at XL184 (cabozantinib), a novel c-Met and VEGFR-2 inhibitor for prostate cancer. There are two randomized trials looking particularly in the postchemotherapy setting. OncoGenex has an antisense that unfortunately showed no survival benefit when combined with docetaxel, but there are reasons why that trial could have come out with similar results in both arms. There are a variety of second-line treatments that could have affected the survival curves, and there is now a second-line trial in combination with cabazitaxel. The agent custirsen is an antisense molecule that targets the protein clusterin, which is a target involved in drug resistance. These are all trials that should read out in the next few years that will have direct implications on patient care.

Cancer Network: Lastly, how do you see the role of chemotherapy evolving in the next 5 to 10 years in the context of novel agents in development and combination approaches that are being tested?

Dr. Petrylak: I think what we really need are molecular markers. There are clearly patients who will respond to chemotherapy after progressing on some of these targeted androgen receptor agents and vice versa. So, you would be wasting your time giving the therapy in that particular group. What we need are molecular markers to determine what the appropriate treatment is for each patient and the particular situation.

Cancer Network: Thank you so much for joining us today, Dr. Petrylak.

Dr. Petrylak: You are welcome.