Addition of chemotherapy to androgen deprivation reduces relapse risk among men with high-risk localized prostate cancer

MUNICH — The addition of four cycles of docetaxel-based chemotherapy to androgen deprivation therapy significantly reduced the risk for clinical relapse or death among men with high-risk localized prostate cancer, according to updated results of the randomized phase 3 GETUG-12 trial presented at European Society for Medical Oncology Congress.

Perspective from Eleni Efstathiou, MD, PhD

An estimated 15% to 20% of newly diagnosed prostate cancers have high-risk features, and outcomes often are predicted by T stage, Gleason score and PSA level. Treatment typically consists of radiotherapy plus androgen deprivation.

Karim Fizazi, MD, PhD, head of the department of cancer medicine at Institut Gustave Roussy in Villejuif, France, and colleagues conducted the GETUG-12 trial to assess the addition of docetaxel plus estramustine — which had improved survival for men with castration-resistant prostate cancer — to androgen deprivation for men with nonpretreated high-risk localized disease.

The trial included 413 men who met at least one of the following criteria: T3-T4 disease, Gleason score of 8 or higher, PSA level of 20 ng/ML or higher, or pathological node-positive disease. All men underwent staging pelvic lymph node dissection.

Researchers randomly assigned 206 men to androgen deprivation for 3 years alone. The other 207 men received ADT in combination with four 3-week cycles of docetaxel (70 mg/m² on day 2) plus estramustine (10 mg/kg daily on days 1-5).

Local therapy was administered at 3 months. The majority (87%) of men received radiotherapy, whereas 25% underwent surgery and 27% received no local treatment.

The groups were well balanced with regard to tumor stage, Gleason score, PSA and node positivity.

RFS served as the primary endpoint.

Initial results, published in 2015 in The Lancet Oncology, showed the addition of docetaxel and estramustine to ADT significantly improved 8-year RFS rate (62% vs. 50%; adjusted HR = 0.71; 95% CI, 0.54-0.94).

At ESMO, Fizazi presented updated RFS data, as well as clinical event information.

After median follow-up of 12 years, 233 men (56%) had an event.

Researchers reported a significantly higher 12-year RFS rate among men who received docetaxel-based chemotherapy (49.4% vs. 36.3%; adjusted HR = 0.71; 95% CI, 0.55-0.93).

Median RFS was 11.6 years (95% CI, 9.1-not reached) among men assigned chemotherapy and 8.1 years (95% CI, 7.3-9.6) among men assigned androgen deprivation alone.

Researchers reported improved median clinical RFS (13.9 years vs. 12.5 years; HR = 0.75; 95% CI, 0.56-0.999).

Researchers also reported higher rates of 12-year metastases-free survival (62.2% vs. 55.8%; HR = 0.81; 95% CI, 0.6-1.09) and 12-year prostate cancer-specific survival (88.2% vs. 83.9%; adjusted HR = 0.7) among men who received ADT plus chemotherapy, but the differences did not reach statistical significance.

PAGE BREAK

A similar percentage of men assigned the combination or ADT alone developed second cancers by 12 years (16.4% vs. 18.8%).

“Very long-term follow-up is needed to assess clinical outcomes in high-risk localized prostate cancer,” Fizazi said during his presentation. “Four cycles of docetaxel-based chemotherapy reduces the risk [for] clinical relapse or death.” – by Mark Leiser

Reference: Fizazi K, et al. Abstract 791O. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Disclosure s : UNICANCER provided funding for this study. Fizazi reports honorarium from and advisory board roles with Amgen, Astellas, AstraZeneca, Bayer, Clovis, Curevac, Essa, Genentech, Janssen, Merck Sharpe & Dohme, Orion and Sanofi. Please see the abstract for all other authors’ relevant financial disclosures.

Perspective

Eleni Efstathiou, MD, PhD

This is a highly important unmet therapeutic need. High-risk localized disease accounts for about 20% of prostate cancer cases, or maybe a little bit more — especially given, in the United States, that we are waiting to see data after the change in U.S. Preventive Services Task Force’s change to its recommendation about PSA screening. Importantly, we know the vast percentage of these men will relapse if they receive single-modality treatment, so we know we must be very thoughtful and mindful and try to combine therapeutic approaches.

All of the societies have tried to reflect with their recommendations and guidelines the need for a therapeutic strategy that is not a single modality, because that likely will not suffice. The European Association of Urology, European Society for Radiotherapy & Oncology, and International Society of Geriatric Oncology have come together to create a more robust guideline perspective, including various options that are available to us, and it can be very confusing. But what becomes obvious is that we need to take into consideration the life expectancy of a man with high-risk localized disease.

In the GETUG-12 trial, the principal investigators tested chemotherapy added to androgen deprivation prior to localized treatment — mainly radiation — at a time when we still did not have a clear indication for docetaxel in the metastatic setting. The researchers wanted to make sure these men were going to be safe, so they applied four cycles of chemotherapy. If one was to design the trial today, obviously they would go for a higher number of cycles, and that may have an impact on the type of outcomes we’re looking at when we compare this approach with ADT alone.

To get to 50% of events after 12 years of maturation is good news for these men. They live longer. It is important that Dr. Fizazi and his collaborators went beyond PSA relapse and provided us with more confidence in the reality of the outcomes. It was quite refreshing to see what looks like an impact in localized disease apart from a delay in metastases.

So what is the take-home message? On the therapeutic side, the clinical relapse-free survival data are very compelling and reinforcing. Given current experience, I think we all feel more comfortable with six cycles of docetaxel. And, Dr. Fizazi and his collaborators gave us another lesson in stellar clinical research: Perseverance is paramount.

Now, has our treatment paradigm for high-risk localized disease changed yet? No. Is it shifting? Yes. In anticipation of neoadjuvant and adjuvant trial reporting, we have a desperate need of molecular classification for both high-end intermediate- and high-risk disease that can further guide our treatment strategies. This is definitely not about chemotherapy versus novel androgen signaling inhibition. Neither is better or worse. This is about developing treatment strategies that can improve the lives of our patients.

Disease classification will be our holy grail. Although it remains elusive, we have a role as physicians to make the most of the data, adapt them to our own practice, monitor patients very diligently because the details do matter, and listen to their own needs.

Eleni Efstathiou, MD, PhD

The University of Texas MD Anderson Cancer Center

Disclosures: Efstathiou reports research support or honoraria from or consultant/advisory roles with Astellas, AstraZeneca, Bayer, Innocrin, Janssen-Cilag, Medivation, Merck Sharpe & Dohme, Sanofi, Takeda and Tolmar.

European Society for Medical Oncology Congress

Read more

Addition of chemotherapy to androgen deprivation reduces relapse risk among men with high-risk localized prostate cancer

Perspective

Related Content