Prostate Cancer Treatment Options Expand With ADT Combinations

David F. Penson, MD, MPH, MMHC

Treatment for prostate cancer has evolved over the past few years to include androgen deprivation therapy (ADT) combined with other agents, such as next-generation androgen receptors, explained David F. Penson, MD, MPH, MMHC.

“There have been a lot of advances in metastatic hormone-sensitive prostate cancer in the last 5 years, even in the last year, regarding how to treat this disease. Specifically, people are realizing that [treatment requires] more than just ADT. It's ADT in combination with chemotherapy with abiraterone acetate (Zytiga) and with certain next-generation androgen receptors,” said Penson.

The phase III ENZAMET trial examined the use of enzalutamide (Xtandi) in metastatic hormone-sensitive prostate cancer and showed improvement in overall survival at 80% versus 72% in patients who received a different nonsteroidal antiandrogen (HR, 0.67; 95% CI, 0.52-0.86; P = .002).¹ Updated data from the ENZAMET trial presented at the 2019 ESMO Congress showed that adding enzalutamide to ADT was associated with modest impairments in fatigue, cognitive function, and physical function, but not general quality of life.²

A similar trial, the ARCHES study, looked at enzalutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer. The ARCHES trial showed that at a median follow-up of 14.4 months, the median radiographic progression-free survival was not reached in those who received enzalutamide versus 19.45 months in patients who were given placebo, translating into a 61% reduction in the risk of radiographic progression or death with enzalutamide (HR, 0.39; 95% CI, 0.30-0.50; P <.0001).³ Updated data presented at the 2019 ESMO Congress demonstrated enzalutamide provides clinical benefit in other areas, though overall survival data is still immature.

In the phase III TITAN trial, results showed that apalutamide (Erleada) plus ADT led to a 33% reduction in the risk of death compared with placebo/ADT in this patient population (HR, 0.67; 95% CI, 0.51-0.89;&#8239;P&#8239;= .0053).⁴ These data led to the FDA approval of apalutamide in September 2019 for the treatment of patients with metastatic castration-sensitive prostate cancer. Updated data of the TITAN trial at the 2019 ESMO Congress showed that health-related quality of life was preserved with the addition of apalutamide, and pain and fatigue were improved.⁵

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Genitourinary Cancer, Penson, the chair of the Department of Urology and the Paul V. Hamilton, MD and Virginia E. Howd Chair of Urologic Oncology at Vanderbilt University Medical Center, discussed the current armamentarium and ongoing research in prostate cancer.

OncLive: What next-generation inhibitors are available to treat metastatic prostate cancer?

Penson: There are 3 [next-generation inhibitors available], including enzalutamide, apalutamide, and darolutamide (Nubeqa), in metastatic hormone-sensitive prostate cancer. We don't have any information yet about darolutamide but we have a lot of information about enzalutamide and apalutamide. The 2 studies on enzalutamide, ENZAMET and ARCHES, plus the TITAN study looking at apalutamide show that both of these agents improve outcomes in men with hormone-sensitive metastatic disease.

How do you determine what agent to give patients?

If you look, it's not just those 2 agents. We also have now abiraterone (Zytiga). We have docetaxel based on STAMPEDE data and LATITUDE data. It comes down to the individual patients. Some patients, for example, have a seizure or epilepsy history, making them ineligible for enzalutamide. Some patients shouldn’t be on prednisone because perhaps they're brittle diabetic.

Some people say higher-volume patients should get docetaxel and lower-volume patients should get the androgen receptor blockers. I don't necessarily subscribe to that theory, but others do. In the end, it becomes the patient’s preference, and sometimes insurance coverage, as well. We want to make sure we do the best for our patients.

Are there differences in safety profile between the drugs?

That's a really important point and a research interest of mine is quality of life and the patient experience. The drugs are very comparable, tend to maintain quality of life, and help patients have a good experience.

There are some adverse events (AEs), however, that will affect patients. For example, enzalutamide is associated with a fair amount of fatigue and that can affect quality of life. Those patients often will switch agents. Apalutamide has a rash in some patients. You'll want to switch [agents]. [The process is] you try out the drug and if the drug has an AE, you switch to one of the other drugs. The great thing about all of these drugs is when you get the right one, the quality of life is maintained and, in the long run, it's probably better than if the patient was just on ADT alone.

What questions remain regarding next-generation agents?

It's not just the next-generation agents. There are a lot of questions out there that are critical related to this. What do we do in the patient who has very low volume oligometastatic disease? Is that a patient who, in addition to these agents, needs local therapy? There's some data showing that local therapy may help. That's a really pressing question in the metastatic space.

In the localized space, are these agents useful earlier on as adjuvant or neoadjuvant therapy? That's going to be a big question that we see over the next 5 to 10 years. It used to be that we had dismissed neoadjuvant hormonal therapy prior to local therapy for prostate cancer. Nowadays, people are saying that maybe with the new agents, it will be effective. That's one of the big questions out there that is going to be answered.

One of the things you have to recognize is a lot of these drugs have the same mechanism of action. You can't combine, for example, apalutamide and enzalutamide. You're hitting the same note on the piano. We want to mix things up a bit.

Is there potential for immunotherapy in the prostate cancer space?

[There are] PARP inhibitors, specifically in the hormone-resistant space with metastatic disease, but immuno-oncology is clearly the future. We can use them earlier when the patients have metastatic hormone-sensitive disease, and perhaps as adjuvant or neoadjuvant therapy with localized disease.

What ongoing trials are happening in prostate cancer?

There are a lot of trials going on, more than I can count. I am really interested in the trial looking at the oligometastatic disease and the role of surgery, the TRoMbone trial. That's going to be very interesting.

There are all these ongoing trials looking at the various checkpoint inhibitors in this space. The future is really interesting. Compared to 10 to 15 years ago when we had almost nothing, now it seems like we're finding new agents and new ways to treat this disease and really getting towards a chronic disease, maybe even cure.

References

1. Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. J Clin Oncol. 2019;37(suppl 18; abstr LBA2). doi: 10.1200/JCO.2019.37.18_suppl.LBA2.
2. Stockler MR, Martin AJ, Dhillon H, et al. Health-related quality of life (HRQL) in a randomized phase 3 trial of enzalutamide with standard first line therapy for metastatic, hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led, international, co-operative group trial. Ann Oncol. (2019) 30 (suppl_5): v851-v934. doi: 10.1093/annonc/mdz394
3. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. Phase 3 study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. J Clin Oncol. 2019;37(suppl 7, abstr 687). doi: 10.1200/JCO.2019.37.7_suppl.687.
4. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13-24. doi: 10.1056/NEJMoa1903307.
5. Agarwal N, McQuarrie K, Bjartell A, et al. Patient-reported outcomes (PROs) from TITAN: a phase III, randomized, double-blind study of apalutamide (APA) versus placebo (PBO) added to androgen deprivation therapy (ADT) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC). Ann Oncol. 2019;30(suppl_5). doi: 10.1093/annonc/mdz248.008.