Multimodal Approaches Emerging in Locally Advanced Prostate Cancer

Edouard J. Trabulsi, MD

Ongoing clinical trials in prostate cancer are adopting multimodal approaches to develop more effective treatments for patients with locally advanced disease, notes Edouard J. Trabulsi, MD. For example, researchers at Thomas Jefferson University Hospital are conducting a trial assessing cabazitaxel (Jevtana) in combination with hormone therapy and radiotherapy in high-risk patients with locally advanced prostate cancer (NCT01420250).

Combination immunotherapy is also being explored in patients with locally advanced disease in a trial of ipilimumab (Yervoy) with or without the PD-1 inhibitor cemiplimab (REGN2810), with stereotactic body radiation therapy (SBRT) followed by surgery (NCT03477864). There is also an arm of REGN2810 alone with SBRT followed by radical prostatectomy.

Other studies could soon further demonstrate that upfront chemotherapy offers increased benefit in high-risk patients with prostate cancer. Specifically, the CALGB 90203/PUNCH trial randomized high-risk patients to hormonal therapy plus docetaxel prior to surgery versus surgery alone. Physicians are awaiting the results of the trial, but it is likely to reiterate the results of CHAARTED and STAMPEDE, predicted Trabulsi.

OncLive: You spoke on locally advanced prostate cancer. What are the main points from your presentation?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Prostate Cancer, Trabulsi, professor, co-director, Multidisciplinary Genitourinary Oncology Center, Prostate Diagnostic Center, vice chair of research, director, Division of Urologic Oncology, Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, discussed emerging multimodal treatment approaches for patients with locally advanced prostate cancer.Trabulsi: I spoke about locally advanced prostate cancer with the intent of defining the meaning of locally advanced disease and how the NCCN guidelines have impacted available treatment options. I also reviewed some of the standard dogmas of treatment and dove into combination and multimodal therapies such as radiation therapy combined with surgery and radiation therapy combined with hormonal therapy.

What is the best way to define locally advanced prostate cancer?

What are some of the recent NCCN guidelines?

What combination trials are exciting?

I also relayed some of the data out of Thomas Jefferson University Hospital on the use of genomics in selecting patients who may benefit from postoperative radiation. I concluded by going over new things on the horizon, specifically clinical trials that are open or coming down the pike looking at combination and multimodal therapy for patients with advanced prostate cancer.Generally, we look at tumor parameters, such as clinical stage on a rectal exam, prostate-specific antigen (PSA), and Gleason score; that gives us an idea of a patient’s risk category. We will incorporate that information with imaging to determine whether a patient’s demonstrable disease outside of the prostate—either on imaging or on physical exam—is high-risk enough to lead to a strong prediction of locally advanced disease.Though the historical data show advanced disease, it doesn’t necessarily reflect dismal outcomes. These patients certainly have choices that offer an optimistic outlook. Generally, the treatments are threefold. There is upfront surgery with the potential for postoperative radiotherapy and/or hormonal therapy, standard external beam radiation therapy (EBRT) in combination with a 2- to 3-year course of androgen deprivation therapy, or a combination of EBRT and brachytherapy with hormonal therapy, as well. Clinical trials follow as a fourth option.We were participants in the CALGB 90203/PUNCH trial and are waiting for those results to report out. The trial enrolled high-risk patients who received preoperative hormonal therapy and chemotherapy followed by surgery. The trial began approximately 10 years ago, before the recent explosion of interest in cytotoxic chemotherapy for early-stage prostate cancer, as seen in the CHAARTED and STAMPEDE trials of docetaxel. It overlaps nicely with those data.

We also did an institutional trial with one of my collaborators, Robert B. Den, MD, investigating the use of the taxane cytotoxic chemotherapy cabazitaxel in combination with hormonal and radiotherapy in high-risk patients on standard radiotherapy. That may turn into a much larger trial and we are waiting to see how that plays out.

Which patients are most likely to benefit from postoperative radiation?

We also have grant funding through the Prostate Cancer Foundation with Adam P. Dicker, MD, PhD, chair of radiation oncology at Thomas Jefferson University Hospitals, looking at a much broader combination and multitargeted strategy of checkpoint inhibition for high-risk patients.Traditionally, we have looked at pathologic features when the prostate is removed, which includes stage. If it’s outside the capsule of the prostate, it’s in the T3 stage. If it’s extended into the vesicle it’s stage IIIB, and if it’s reached the lymph nodes it’s stage IV.

We will look at the surgical margin status. Patients with positive margins are at a very high risk of recurrence. There have been several large, randomized trials in the United States and Europe looking at patients who fit this category. These trials randomized patients in the adjuvant setting to postoperative radiotherapy versus observation and show at least a PSA benefit.

The US trial showed decreased rates of metastasis and improved survival in patients who received postoperative radiotherapy. However, this has not been widely incorporated into care pathways. Many urologists are very concerned about postsurgical side effects and overtreatment with the addition of radiation. Many of these men are cured with surgery alone, so the additional therapy may not be necessary if PSA can differentiate between who needs it and who doesn’t.

It's a very controversial topic and may help define genomics’ role in practice. Dr Den and our group, in combination with other academic centers, have looked at that extensively. Retrospective matched-pairs analyses are investigating how the genomic classifier may impact practice. Very low rates of development of metastatic disease do not seem to be hugely impacted by the low-risk genomic classifier and subsequent administration of radiation for cause in the salvage setting, versus preemptively in the adjuvant setting.

What does the future hold 5 years from now?

However, patients who have a high-risk classifier seem to have a tremendous benefit if they received early radiation. That has become one of our local standards in helping us decide who to give radiation to postoperatively. The concept of accommodation and multidisciplinary care really should be the focus and reality going forward. Incorporating all specialists, not just the surgeons and radiologists, but medical oncologists is important. The idea of systemic therapy and the combination of local therapy is getting a lot of traction. This multimodal combination therapy mantra is going to become much more widespread going forward.