Sequencing Questions Remain in Prostate Cancer Paradigm

Christopher J. Sweeney, MBBS

The FDA recently expanded the approval of abiraterone acetate (Zytiga) to include the treatment of patients with metastatic high-risk castration-sensitive prostate cancer, based on findings from the phase III LATITUDE trial.

In the study, 1199 patients were randomized to receive androgen-deprivation therapy (ADT) plus either abiraterone/prednisone or placebo. There was a 38% reduction in the risk of death with the addition of abiraterone and prednisone to ADT compared with ADT alone. After a median follow-up of 30.4 months, the median overall survival was not yet reached with abiraterone acetate versus 34.7 months with placebo (HR, 0.62; P <.001).

OncLive: How do you determine whether to administer docetaxel or abiraterone to patients with prostate cancer?

In an interview with OncLive, Christopher Sweeney, MBBS, a medical oncologist at Dana-Farber Cancer Institute, discussed the role of abiraterone for patients with hormone-sensitive prostate cancer, and what physicians should consider when choosing between abiraterone and docetaxel.Sweeney: Determining between abiraterone and docetaxel is a challenge, as both drugs work well. Abiraterone is an easier drug for most patients to tolerate because it is a hormonal therapy. Docetaxel also has activity, but it has a higher treatment burden.

Abiraterone is a pill you take daily for many months but has some long-term side effects, such as rising blood pressure. Docetaxel is given for 6 cycles every 3 weeks, but has the common side effects of chemotherapy such as fatigue, weakness, risk of lowering the white cell counts, and neutropenic fever.

Which drug you go with is a topic of big discussion in the community. Once a person progresses, you tend to alternate to the other agent. The other big question here is the cost of these therapies. Docetaxel for a course of 6 cycles is close to $10,000, whereas for 1 month of therapy with abiraterone, it is about $8000. If you are on abiraterone for 3 years, the final cost will depend upon the patient’s copays and out-of-pocket expenses. It is a very complicated financial proposition that may arise when you discuss it with patients, especially when it is over a 3-year period, which is the average amount of time that patients were on abiraterone when they started with hormonal therapy.

If you start with docetaxel and put the patient on a treatment break and the prostate-specific antigen starts to rise, you can add abiraterone. The patient may only be on it for an average of 18 months, which is half the time of when you would start abiraterone upfront. It is a complicated conversation with balancing treatment burden, the ability to receive docetaxel, and the cost of therapy to the institutions and patients.

How big of a factor is financial burden when you are making treatment decisions?

Which drug is given more frequently?

Either option is appropriate, but it is important to tailor the decision to the patient’s situation, their financial and physical capabilities, and preference.It is a complicated conversation. I will write the prescription and send it to the pharmacy who will determine if it needs an approval. Then, it will go to the billing department, which will determine a patient’s out-of-pocket expenses depending on their coverage. Some patients have no insurance or have no viability of being able to access it. Most of these patients are on Medicare. Their first bill may be something like $10,000, and the cost is much less once they are past that. It is a complicated conversation that often takes a couple of weeks to resolve.This is the subject of many conversations and debates around the world. The fashionable answer is the drug that has the lower treatment burden, abiraterone, is given more. It is a simple hormonal therapy and most patients would be able to tolerate it better than docetaxel. It is easier to give when you think about it from a short-term toxicity perspective. However, we may need to sit back and ask, “What is the bigger and more profitable long-term plan?”

Why should you give docetaxel first?

As the data unfolds, it is [important to get] access to as many of the therapies as possible, whether it is abiraterone, enzalutamide (Xtandi), radium-223 dichloride (Xofigo), sipuleucel-T (Provenge), or docetaxel. When a patient starts hormonal therapy, that is when they are at their fittest, can tolerate docetaxel, and you may be able to bring in the other treatments later. Whereas, if you start with abiraterone, they may get more frail with time and not be a docetaxel candidate. The longer-term plan may be to play the harder card first.It is cheaper, the patient is the most fit, and they are done with the therapy in 6 cycles and are then put on the hormonal therapy and are not at risk for the longer toxicities involved with continuous abiraterone. It is a hard conversation. Docetaxel is a generic drug and is old-style chemotherapy.

Many regions around the world cannot access abiraterone because they have governed payer systems, such as in the United Kingdom (UK), parts of Europe, and Australia, where they look at the pricing and say, “It is clearly much easier to give docetaxel in terms of cost since you get the same effect.”

How do you handle problems with adherence with the oral therapy?

There is a study that has been conducted in the UK, where they have patients who received ADT with docetaxel and, at the same time, patients were randomized to an arm of ADT and abiraterone. That is the most direct evidence that we have, although it is not a perfect randomized study, showing that the outcomes are the same whether you lead with docetaxel or abiraterone. Adherence is somewhat easy to manage if you can see that they are responding well. If a patient is responding, you could put them on a treatment break but we do not know if it is viable. If a person is on long-term abiraterone, it is something worth considering. If they have a deep response and are experiencing side effects, you can reintroduce abiraterone with the hormonal therapy later.

What next steps can be taken to improve adherence, and the treatment of prostate cancer in general?

However, it is a difficult conversation when the adherence may be driven by choosing to pay the rent or the food versus the bill for abiraterone. Again, it is a conversation where we need to think of whether the physical side effects the patients are having or the financial implications are leading to the lack of adherence.Can we get to a period where we give all 3 drugs, testosterone suppression plus docetaxel and abiraterone, to get the patient into a deep remission and have them on a treatment break? Their quality of life will be better off with these therapies and the financial implications will be less. Hopefully, they have a greater effect with longevity because the cancer has been put into a deeper remission because we used all the therapies upfront. That is the most plausible next project that we have.

We have number of studies with testosterone suppression plus or minus enzalutamide. The physicians and patients decide if they want to receive docetaxel. There is a study in France with a similar data set, but they are using abiraterone. That data set should possibly come out in the next 12 months for those 2 studies and we can combine the 1000 patients who got ADT and docetaxel versus ADT, docetaxel, and abiraterone to determine if a triplet is better than a doublet.

Are there biomarkers from the tumor that determine which treatment a patient should be given? That is the other area of work that is ongoing. We are analyzing the tumors to see which patients needed more intense therapy.

Where are we currently with biomarkers in prostate cancer?

We also know that if the patient has certain features, they will do better than others. For example, if a patient presents with a high burden of metastatic disease, then median survival on hormonal therapy is about 3 years. If they have a high burden but relapse after the local therapy, their median survival is over 4 years. If you have a low-volume disease when you present with metastatic disease the median survival is over 4 years. However, if you have a late relapse and a low-burden of disease, the median survival is about 8 years and some of those patients could be treated with hormonal therapy plus radiation to the metastatic lesion and do well for many years. There are a few that have come forward. The one that we know most about is DNA damaged-repair genes and those are being paired with PARP inhibitors. The other biomarker that is quite active is PTEN loss and pairing that with an AKT inhibitor or PI3-kinase inhibitor.

Fizazi K, Tran N, Fein LE, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi: 10.1056/NEJMoa170417.