Petrylak Shares Selection Considerations for Available Agents in Hormone-Sensitive Prostate Cancer

Daniel P. Petrylak, MD

The use of abiraterone acetate (Zytiga), enzalutamide (Xtandi), and apalutamide (Erleada) can lead to improvements in overall survival (OS) and progression-free survival (PFS) in patients with hormone sensitive prostate cancer, according to Daniel P. Petrylak, MD, who added that decisions regarding selection for these agents should consider toxicities and regulatory status.

“When choosing between abiraterone, enzalutamide, apalutamide, and docetaxel, [we need to consider] the [expected] adverse effects [AEs], how we plan to manage them, and the financial implications on our patients. All of these factors come into play,” Petrylak explained. “Notably, one difference between enzalutamide and apalutamide is that there is slightly less central nervous system [CNS] penetration with the latter. Darolutamide has the least penetration, but we don’t have an FDA approval for the use of the agent in this space yet.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Prostate Cancer, Petrylak, a professor of medicine and urology and coleader of Cancer Signaling Networks at Yale Cancer Center, discussed pivotal trials that have read out in hormone sensitive prostate cancer, recommendations for selection, and unanswered questions to address with future research efforts.

OncLive^®: What is the current role of abiraterone in the treatment of patients with metastatic castration-naïve and hormone sensitive prostate cancer?

Petrylak: In 2 randomized trials, we have seen a significant improvement in survival [with this agent], with about a 30% reduction in the risk of deaths. This is similar [to what has been seen with] many of the other agents used in the space; the confidence limits overlap. One issue with abiraterone is cardiovascular toxicity. As demonstrated in research by the Fox Chase group, there is a higher rate of cardiovascular events in those who have pre-existing cardiovascular conditions. It’s critical to keep this in mind when choosing between available agents.

What were the lessons learned from the LATITUDE, STAMPEDE, and CHAARTED trials? How do you weigh these different options in practice?

All these trials demonstrated a similar overall survival (OS) benefit. The CHAARTED study used docetaxel [plus androgen deprivation therapy (ADT)] and demonstrated a better OS in those patients who have high-risk disease, which is defined as having more than 4 lesions on bone or skin, and/or the presence of visceral metastases, particularly liver metastases. The LATITUDE and STAMPEDE trials evaluated abiraterone. The first rendition of STAMPEDE used docetaxel for about 10 cycles and the CHAARTED trial had about 6 cycles. STAMPEDE did not stratify patients based upon their risk factors. However, those survival improvements were associated with docetaxel.

When you [weigh] these trials, financial toxicity is an issue. Abiraterone is an expensive drug because it’s not [available for] infusion like docetaxel. Docetaxel is generic right now and so is abiraterone, to some degree. Some patients only want 6 cycles of chemotherapy; they do not want to worry about long-term hypertension and liver function abnormalities. As such, [decisions] depend on the AEs, how those toxicities are going to be managed, and how treatments are going to be administered. [We also need to keep in mind the] goals of the patient and what they are willing to tolerate.

You mentioned that abiraterone is associated with cardiovascular disease and mortality. How does this factor inform decisions pertaining to selection?

Defining how we manage cardiovascular risk is one of the major challenges faced in this disease. We may see the risk, but how do we prevent it? At this point in time, we do not have a good answer to that question. We tend to shy away from drugs that would precipitate this risk.

Now we've got gonadotropin-releasing hormone receptor agonists, such as relugolix [Relumina], which is an orally administered agent that has fewer cardiovascular AEs. Should these drugs be differentially administered to patients who have had an [myocardial infarction] within 6 months or a history of congestive failure? This needs to be examined carefully so when the oncologist sees a patient, they can determine whether they should treat them alongside a cardiologist or whether the they should be referred elsewhere. Also, is there any pre-treatment screening that should be done? At this point, we do not have answers to any of these questions.

We may have insight on what agents should not be used or avoided. However, we don’t know whether a patient who is put on abiraterone should receive acetylsalicylic acid [Aspirin]. Clearly, we are going to control our patients’ blood pressure and diabetes. However, if someone is hypertensive and diabetic to begin with, we should stay away from abiraterone.

Could you speak to the ENZAMET trial and how it compares with other trials in the space?

This study took patients who had hormone-sensitive disease and randomized them to receive [testosterone suppression plus] either enzalutamide or a nonsteroidal antiandrogen therapy. Again, a similar improvement in survival was seen [with enzalutamide].

The difference between LATITUDE and the STAMPEDE trials, is that the former allowed for prior docetaxel therapy and the survival benefit was seen irrespective of whether patients received docetaxel or not. The real question is: How much benefit does docetaxel add to this particular treatment? To date, the answer is not clear.

There does seem to be an improvement in progression-free survival [PFS], but, at this point in time, there's no difference in OS. This trial provides more of a retrospective look [at the situation]; thus, [it is] questionable whether docetaxel is truly needed in this situation. This differs from the ARCHES trial, which had radiographic PFS [rPFS] as its primary end point. The primary end point of OS has not yet been reached but it showed similar data to that of ARCHES from a rPFS standpoint. 

Shifting to darolutamide (Nubeqa), compare with some of the other agents in this space?

This agent has only been approved in the non-metastatic castration-resistant prostate cancer space; this may set the drug apart from the other 2 [antiandrogens], but we don’t have randomized data comparing them yet. We need to see more studies.

There may be less fatigue with apalutamide due to the penetration across the CNS; however, the cost comes in the form of increased thyroid function tests, such as higher thyroid-stimulating hormone and hypothyroidism, and a potential skin rash. As such, both of those AEs need to be [weighed] with those associated with docetaxel and abiraterone.

Are there any emerging approaches that you are excited about and wanted to highlight?

Several different trials are examining several questions in this area. Does the addition of radium up front provide a better survival [benefit]? Is the addition of a PARP inhibitor in the treatment of patients with BRCA1/2 mutations provide added benefit? Do checkpoint inhibitors have a role here?

Studies are looking at pembrolizumab in this setting, along with enzalutamide. Are we going to see more benefit if we move other agents with different mechanisms of action to the frontline setting? This is still not clear and needs to be investigated further. We have been surprised by some of the results so far, but we need more data.

Is there anything else that you would like to add?

You must have a discussion with all patients about the use of docetaxel, abiraterone, enzalutamide, and apalutamide. I was surprised when I heard that only about 30% to 40% of patients in the United States receive one of these agents. I believe we are doing our patients a disservice by not giving them all the facts; it is truly up to them to decide. These options should be offered to everyone and the risks and benefits of each option need to be discussed.