Role of Chemotherapy Remains Strong in High-Risk Localized Prostate Cancer

Howard M. Sandler, MD

Adjuvant treatment with docetaxel and prednisone has a significant survival benefit in patients with localized, high-risk prostate cancer, demonstrating that chemotherapy continues to play an effective role in improving outcomes for patients.

Results of a phase III trial, which was were presented during the 2015 ASCO Annual Meeting, showed that the treatment had a 4-year overall survival rate of 93% and was associated with an acceptable safety profile, as well.

“These are men who have high Gleason scores, high prostate-specific antigen (PSA) levels, or locally advanced cancer—those without metastases,” says lead study author Howard M. Sandler, MD. “However, they are the patients who are likely to develop metastasis, and these are potentially the men who will die from prostate cancer. Preventing metastasis and curing them of their local disease is really important.”

OncLive: What kinds of strategies are being used to tackle high-risk localized prostate cancer?

Is chemotherapy commonly used alone or in combination with radiation and hormone therapy?

Sandler, who is chair, Department of Radiation Oncology, professor of Radiation Oncology, Cedars-Sinai Medical Center, spoke on locally advanced prostate cancer during the 2016 OncLive State of the Science Summit on GU Cancer. In an interview with OncLive, he sheds light on maximizing outcomes for patients with locally advanced prostate cancer, the evolving role of chemotherapy, and the steps to take once disease turns metastatic.Sandler: Options today for high-risk localized prostate cancer include radiation therapy, usually with long-term androgen deprivation therapy of 2 to 3 years, or surgery in select patients in which the cancer hasn’t extended too far outside the prostate. Those would be the standard approaches. We know that those work sometimes, but the overall success rate leaves something to be desired. Today, I mentioned the potential role of chemotherapy in men with locally advanced prostate cancer who are getting radiation and hormone therapy, and who might be candidates for adjuvant chemotherapy after radiation is completed.The role of chemotherapy for men with localized high-risk prostate cancer is very interesting. After all, chemotherapy is widely used in the other big 4 cancers. For example, in breast cancer, adjuvant chemotherapy is standard. In lung cancer and colon cancer, chemotherapy is also standard. Prostate cancer has been an outlier, in that chemotherapy has not yet found a role for men without metastatic disease until relatively recently. Chemotherapy was established in men with metastatic castration-resistant prostate cancer, and docetaxel was shown to improve survival in those very advanced men.

Is it commonly used in cancer centers across the nation or are we still trying to get a bigger uptick of it?

As an oncologist, how do you sit down with a patient and determine if he is a good candidate for chemotherapy, and if he’s going to be able to tolerate it? What are some of the things to take into consideration?

A study that I reported on in 2015 and also presented today showed the survival data for adjuvant docetaxel chemotherapy after radiation for high-risk localized prostate cancer. We observed a small but statistically significant improvement in overall survival. This was at a 4-year endpoint, which is very early in prostate cancer. It’s my expectation that the survival curves, which are already separating by 4 years, are going to separate more over time. Therefore, I think that the impact of chemotherapy is measurable. It’s statistically significant. In fact, it’s already been listed in the NCCN guidelines as an option for men with high-risk localized prostate cancer.I think it’s commonly discussed. I am not sure how often it’s being used. In my view, it shouldn’t be used in everyone. In selected patients—those who are especially likely to tolerate the chemotherapy well—who are interested in an aggressive approach to their high-risk prostate cancer, chemotherapy might be ideal for them. For men who are older, less fit, and less likely to tolerate chemotherapy, perhaps the risk benefit ratio doesn’t favor using chemotherapy in those patients.Chemotherapy tolerability is probably associated with general measurements of overall fitness and other comorbidities, such as diabetes, heart disease, or previous hospitalization—things that you would suspect might lead to increased toxicity with chemotherapy would be relative contraindications, in my opinion.

How have chemotherapy regimens evolved over the last couple of decades?

Chemotherapy with docetaxel is very, very common. One of the benefits for using docetaxel after prostate cancer is that medical oncologists are super familiar with it. It’s not anything new for them. Medical oncologists are probably pretty comfortable giving chemotherapy, and they likely have a pretty good judgment as to who they feel would be good candidates.Chemotherapy in prostate cancer has had trouble getting fully established. Back in the 1990s, there were a number of different chemotherapies that were being used. The level of evidence was pretty weak. They were phase II studies [that showed that] chemotherapy could lower PSA, but there was no proven survival advantage.

In 1999, along with a medical oncology colleague of mine, Dr Kenneth Pienta, we designed a study to test whether chemotherapy with paclitaxel and estramustine (Emcyt) would be beneficial in a man with high-risk prostate cancer, along with radiation. We tested that chemotherapy and there was some toxicity associated with estramustine, so we didn’t achieve our full accrual goal. However, 400 men participated and, at 10 years, there was no survival advantage.

Where do you see treatment of high-risk localized prostate cancer going in the future?

What are the barriers to achieving this in the treatment of the disease?

It turned out that estramustine was probably not the best chemotherapy. Ultimately, in other studies, docetaxel was proven to be more effective and improve survival. Then, we added docetaxel to that localized disease model. In high-risk localized men who were getting radiation and hormone therapy, we used docetaxel instead of the paclitaxel/estramustine combination, which was probably a more effective treatment approach. When we completed that study without toxicity, we did see a survival benefit.There is a lot going on in prostate cancer, which is a good thing. Currently with radiation therapy, we are using a standard hormonal therapy—which is an LHRH agonist, such as goserelin acetate (Zoladex) or leuprolide acetate for depot suspension (Lupron). Those are the drugs that are most commonly used. Yet, they may not be the best hormonal therapy agents. My expectation is that for men at high risk, we are going to escalate the hormonal therapy with drugs such as enzalutamide (Xtandi) or apalutamide. When those drugs are used in randomized trials, they will likely show a benefit above our current hormonal therapy. Optimization of hormonal therapy is 1 strategy.There are 2 main barriers to doing better for localized disease. Are we achieving the optimal local control? Is the radiation good enough to eliminate cancer where the prostate sits? We know there is room for improvement in local therapy.

The second barrier is that men with high-risk localized disease often have subclinical metastatic disease. Therefore, enhancing the treatment of small-volume metastatic disease is going to be important.

How does treatment shift once the disease becomes metastatic?

One way to break down that latter barrier is to do better imaging. I do believe that imaging is going to improve, so small metastatic deposits might be detected via imaging and treatable in a way that can improve outcomes.If I see a patient with localized disease, I’m hoping that they have no metastatic disease and they are curable. If someone has metastatic disease, our focus shifts because the expectation is that the disease has spread in such a way that local control can’t eliminate the disease. Perhaps most of those patients are incurable. Therefore, the focus is different when it’s localized and potentially curable, and [when it is] metastatic, it is likely incurable.

Sandler HM, Hu C, Rosenthal SA, et al. A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521). J Clin Oncol. 2015;33 (supp; abstr LBA5002).