Yu Previews Future of Castration-Naive Prostate Cancer

Evan Ya-Wen Yu, MD

The CHAARTED, STAMPEDE, and LATITUDE trials have manifested in a dramatic clinical benefit for patients with metastatic castration-naïve prostate cancer, explained Evan Y. Yu, MD, enabling physicians to turn their attention toward those with oligometastatic disease, earlier detection, and the potential for metastatic therapy.

In the phase III LATITUDE trial, the addition of abiraterone acetate (Zytiga) and prednisone to standard androgen deprivation therapy (ADT) resulted in a 38% reduction in the risk of death versus ADT alone.¹ The findings served as the basis for the February 2018 FDA approval of abiraterone for patients with metastatic high-risk castration-sensitive disease.

The STAMPEDE trial further investigated the use of abiraterone in this patient subset and demonstrated a 37% reduction in the relative risk of death when added to standard ADT in patients with high-risk hormone-naïve prostate cancer.²

The CHAARTED trial took patients with metastatic hormone-sensitive prostate cancer and randomized them to receive either ADT plus docetaxel or ADT alone. At a median follow-up of 53.7 months, overall survival (OS) results revealed a median OS of 57.6 months versus 47.2 months with the combination of docetaxel and ADT and ADT, respectively.³

“What I tend to do is take patients who have high-volume metastatic disease and offer them either docetaxel or abiraterone [after accounting for] comorbidities, side effects, cost issues, and practicality issues,” said Yu. “About half of my patients opt for docetaxel and half opt for abiraterone. For patients with low-volume disease, I feel the data are stronger and I offer them abiraterone.”

Considering the recent success in the metastatic space, Yu explained that the next wave of research will focus on earlier detection and intervention for those with oligometastatic and low-volume disease.

OncLive: What are the current therapies used in patients with metastatic castration-naïve prostate cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Yu, a professor in the Department of Medicine, Division of Oncology, University of Washington, Seattle Cancer Care Alliance, discussed the available options for patients with metastatic castration-naïve prostate cancer.Yu: Metastatic castration-naïve prostate cancer is a disease state we're seeing more and more of as time goes on, partially because there's less prostate-specific antigen (PSA) screening. As a result of that, we're seeing patients with an unmet need. Recently, there have been quite a bit of exciting data looking at adding therapies to standard ADT. We've seen that docetaxel has led to a dramatic survival benefit when added to ADT in both the CHAARTED and STAMPEDE trials. When added to ADT, abiraterone with prednisone also [results in] a dramatic survival benefit, as seen in LATITUDE and in an arm in STAMPEDE.

This leads to a little bit of a clinical dilemma, in which one asks whether we should use docetaxel or abiraterone. At this point in time, a few things are clear. For high-volume or high-risk metastatic disease, patients gain a survival benefit from docetaxel; that’s not clear for patients with low-volume disease. In the CHAARTED trial, high-volume was defined as 4 or more bone metastases with at least 1 outside the axial skeleton or visceral lesions.

At the same time, there are clear data from the LATITUDE trial, which showed that patients with high-volume disease as well as high-risk patients have a survival benefit from abiraterone. High risk was defined as 2 of 3 criteria: either a Gleason score of 8 or greater, 3 or more bone metastases, or visceral lesions. Posthoc analyses presented at the 2018 ESMO Congress showed a clear survival benefit with abiraterone in patients with low-volume or low-risk disease.

Now, the next step is to evaluate the new data on oligometastatic treatment. We already have data in colon cancer and other cancers, such as lung cancer, but the data are unclear in prostate cancer. [However], trials are ongoing, and some of them are also looking at eradicating the primary lesion of the prostate. Theoretically, there's a rationale for this, because the primary will shed lesions—micrometastases—that will set down and create more metastases. Ablating those [metastases] at a lower-volume disease state might be ideal. With that being said, there are studies reading out [that are evaluating] ablation of the primary prostate lesion of a patient with metastatic disease.

The HORRAD trial was negative for those with high-volume disease or those with a high prostate-specific antigen (PSA) greater than 20. The median PSA was in the 50s. With that being said, there was an arm in the STAMPEDE trial where patients were given lower doses of radiation, such as 55 Gy over 4 weeks to the prostate.

In the subgroup analysis, this showed a survival benefit. Overall, [HORRAD was] a negative study, but that subgroup analysis leads to a strong hypothesis that we should ablate the primary lesion even in patients who have very low-volume metastases and oligometastases.

How can we move more toward early detection and metastasis-directed therapy?

As the field moves toward next-generation imaging modalities, with new PET imaging like prostate-specific membrane antigen (PSMA)-PET and fluciclovine PET, we're going to be able to find really low-volume disease. If we do primary ablation and ablate those oligometastases, we might not only improve survival outcomes, but we may actually cure more people.Traditionally, we've used standard CT scans and bone scan imaging, but we recognize they lack sensitivity. More recently, we've seen data with next-generation PET imaging radiotracers that have been much more sensitive, including fluoride PET, which is much more sensitive for finding bone metastases. We've seen that choline and acetate PET are much more sensitive for lymph node metastases, and more recently, fluciclovine, which is a marker of amino acid synthesis and was FDA approved for [patients with] recurrent prostate cancer. It could probably could find metastases as early as 0.5 [ng/mL]. Certainly, by 1 [ng/mL] or 1.5 [ng/mL], you're doing a pretty good job of finding metastases.

Have other combinations been proposed with abiraterone and docetaxel?

PSMA is ubiquitously expressed on prostate cancer cells. Gallium-68 PSMA and 18F-PSMA PET imaging radiotracers might be able to detect the lesions around 0.5 PSA or even lower. Once we start [using] more of those imaging modalities, which are being used in other countries, such as Australia, New Zealand, and Germany, we can start using them to design clinical trials. Then, we can ask whether we can identify those metastases earlier, whether we can do something about it, and whether that could lead to better outcomes.In terms of combination therapy for [patients with newly diagnosed] metastatic prostate cancer, the abiraterone and docetaxel data are just the start. There are multiple trials ready to read out soon. Neeraj Agarwal, MD, of Huntsman Cancer Institute, has the SWOG 1216 trial that looks at TAK-700, which is a similar agent to abiraterone. We'll see results from that trial very soon. We'll also see results from the ENZAMET trial, which is being led by Christopher Sweeney, MBBS, of Dana-Farber Cancer Institute. ENZAMET is looking at adding in enzalutamide to a LHRH analog as first-line ADT.

What does the future hold?

There are other trials that are evaluating combination therapy; for instance, apalutamide (Erleada) or darolutamide early with chemotherapy. In the future, we might see a combination of standard ADT, a potent androgen receptor (AR) agent, and abiraterone or enzalutamide, apalutamide, or an AR blocker and a taxane chemotherapy.The future of this field is not just consolidation and intensification of systemic therapy. As a medical oncologist, I love our new systemic therapies, but the field is all about putting it together to offer a multidisciplinary and multimodality therapy [that will allow us to] eradicate the cancer and cure more people. That includes surgery. Should we be doing more laparoscopic lymph node dissections in patients who had some oligometastatic lymph nodes? It also includes the use of radiation. We have to do the studies so that down the road we will cure a lot more people. That's the hope.

References

1. Fizazi K, Tran N, Fein L, et al; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi: 10.1056/NEJMoa1704174.
2. James ND, De Bono JS, Spears MR, et al; STAMPEDE investigators. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE (NCT00268476). J Clin Oncol. 2017;35 (suppl; abstr LBA5003). doi: 10.1200/JCO.2017.35.18_suppl.LBA5003.
3. Kyriakopoulos CE, Chen YH, Carducci MA, et al; CHAARTED investigators. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED Trial. J Clin Oncol. 2018;36(11):1080-1087. doi: 10.1200/JCO.2017.75.3657.