Hormonal Agents Improve Survival in mCSPC, but Novel Targets Are Needed For Further Drug Development

Neeraj Agarwal, MD

Although intensified therapy with hormonal agents like apalutamide (Erleada), enzalutamide (Xtandi), and abiraterone acetate (Zytiga) has improved survival in patients with metastatic castration- sensitive prostate cancer (mCSPC), new targets and novel approaches are necessary for those who progress on these agents, according to Neeraj Agarwal, MD.

“By moving novel hormonal therapies to the up-front setting, we have seen a dramatic improvement in the overall survival [OS] of patients with mCSPC,” said Agarwal. “Novel hormonal therapies such as apalutamide, enzalutamide, and abiraterone are improving survival and delaying disease progression, without compromising quality of life; this is great news for our patients.”

Research efforts dedicated to improving outcomes include further examination of PARP inhibitors for patients with metastatic castration-resistant prostate cancer (mCRPC) who harbor mutations in DNA repair genes, as well as novel immunotherapy combination regimens like cabozantinib (Cabometyx) plus atezolizumab (Tecentriq), and pembrolizumab (Keytruda) plus olaparib (Lynparza).

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on prostate cancer, Agarwal, a professor of medicine and director of the Genitourinary Oncology Program at the Huntsman Cancer Institute, discussed the role of docetaxel in the frontline setting, the emergence of hormonal agents in the paradigm, and efforts being made with combination regimens to potentially treat patients with resistant disease.

OncLive^®: Does docetaxel still play a role in mCSPC treatment or has it been upstaged by the emergence of novel hormonal agents?

Agarwal: The CHAARTED trial [NCT00309985] resulted in the shift of docetaxel to the up-front setting; this was truly a paradigm-shifting trial. For the first time, [results] showed that by moving drugs that are approved in the metastatic setting to the up-front setting, a dramatic improvement in OS will be observed. However, the use of docetaxel has not picked up in the real-world setting.

During the 2020 American Society of Clinical Oncology Virtual Scientific Program, data indicated that only 4% of patients with mCSPC, in the real-world setting, actually received docetaxel. This was after the CHAARTED trial data read out. Even in other countries, such as the United Kingdom, a majority of patients do not receive docetaxel chemotherapy, although many countries’ state-sponsored health care systems provide this option for free.

This brings up an important point: Why not? I believe it’s a combination of tolerability, [patients’] age, the willingness to try docetaxel chemotherapy up front, and apprehensions about the long-term adverse effects like neuropathy and neutropenia. Docetaxel is a drug that led to a new way of thinking, especially in terms of how to treat patients with mCSPC. Even so, it has been replaced by these novel hormonal therapies such as apalutamide, enzalutamide, and abiraterone.

Could you expand a bit on the STAMPEDE and CHAARTED trials? How did this research lead to the development of newer agents for use as intensified therapy in this setting?

STAMPEDE [NCT00268476] is a very well-organized trial that is composed of multiple arms. Arms keep getting added and inefficient arms are also being removed. This is a big umbrella trial that is trying to determine whether docetaxel can be moved to the up-front setting. This trial includes not only patients with newly diagnosed disease, but those who have locally advanced disease, nonmetastatic disease, and lymph node–positive disease.

The STAMPEDE population is more heterogeneous compared with that of the CHAARTED trial. The former showed that docetaxel improved OS in patients with metastatic prostate cancer. Again, it remains to be seen why this has not led to an uptake of docetaxel in a majority of patients in the United Kingdom. We are asking the same question with regard to the CHAARTED trial in the United States.

These trials were the first to show that intensified therapy in the mCSPC setting improves OS, and that has actually led to the advent of newer drugs such as apalutamide, enzalutamide, and abiraterone being used as intensified therapy in this setting. However, docetaxel use itself has not picked up; in fact, its use is slowing down even more now. For example, I have not used docetaxel chemotherapy in more than a couple of patients in the past 6 or 7 months, especially in light of the coronavirus disease 2019 pandemic.

There is a huge reluctance for my patients to go with docetaxel if they [can receive] an oral pill like apalutamide that doesn’t require them to come in for a visit.

What was the significance of the LATITUDE trial?

LATITUDE [NCT01715285] was the first trial to test abiraterone in patients with high-risk mCSPC. The risk status was defined as 3 or more bone metastases, a Gleason score of 8 or more, or visceral metastasis. Patients had to have 2 of these 3 features in order to qualify for the trial. In this setting, the use of abiraterone improved radiographic progression-free survival and OS. The trial basically reestablished that intensifying therapy with novel hormonal therapies improves survival in this setting.

Does using abiraterone present any challenges?

We can all agree that the dose of prednisone [that is given with abiraterone] is pretty low, but even low-dose prednisone is known to make the risk of diabetes high. It could also make hypertension or cardiovascular health status worsen over time—and we already know that androgen deprivation therapy itself is associated with an increased risk of cardiovascular events. Prednisone has to be taken for months to years, and we don’t know how extensive an effect its chronic use will have on our patients. As such, in my opinion, this remains a concern.

Another concern with abiraterone, which I have noticed over the past 7 to 8 months during the pandemic, is that my patients don’t want to come into the hospital every 15 days for [laboratory work], and they are required to do so for the first 2 to 3 months that they receive the agent. These lab [values] have to be monitored pretty aggressively when we start someone on treatment. Therefore, this is another discouraging factor associated with the agent.

Where should future research efforts be focused now that the up-front use of hormonal agents has extended survival for these patients?

With the movement of novel hormonal therapies, such as apalutamide, enzalutamide, and abiraterone, to the up-front setting, our patients are living longer and not experiencing disease progression within 16 months. Ultimately, these patients are also maintaining their quality of life. However, we are increasingly seeing patients who are experiencing disease progression on these therapies. When they develop metastatic castration-resistant disease after being treated with apalutamide or enzalutamide, they are a challenge to treat. Looking forward, we must determine how to find novel targets to further drug development.

Results from large, randomized trials led to the recent approvals of the PARP inhibitors olaparib and rucaparib [Rubraca]. These [agents are] for patients with mCRPC who harbor mutations in DNA repair genes. This is only a small number of patients, so we need other targets to identify. PTEN deficiency is another target, which will be exploited very soon. Hopefully, we’ll have a drug available in the clinic for these patients [in the future]. This is just a starting point. Novel targets need to be identified and drugs will need to be developed.

Immunotherapy has come a long way. We saw data from the phase 1 trial examining AMG 160, which is targeting PSMA and engaging cytotoxic T cells. Androgen receptor degraders also seem very promising to me. I had the chance to present data on cabozantinib and atezolizumab in the mCRPC setting. A phase 3 trial has already started using this combination regimen, along with another one that I’m excited about: pembrolizumab and olaparib. These are newer drugs, with newer mechanisms of action, and newer targets. A lot of work must be done to accrue patients to these trials so that these therapies can receive regulatory approval.