At the time this study started, docetaxel had promising results for metastatic prostate cancer (castration-resistant initially, then even for hormone-sensitive). It had demonstrated significant overall survival (OS) benefit, especially in conjunction with estramustine (to limit neutropenic fever).
Based on this, the following was the study trial design:
Some important things to note are:
1) Inclusion criteria allowed for Gleason 7 prostate cancer
2) Patients had pelvic LND prior to randomization to stratify based on pN status
3) PSA > 20 (higher cutoff than some other studies)
4) Docetaxel was just 4 cycles (as it had not yet been established in metastatic disease) and was given with estramustine
5) Local treatment could have been either radiation or prostatectomy
- If pN-, either radiotherapy or prostatectomy
- If pN+, radiotherapy or observation
- Of note, 87% of patients got radiotherapy
6) ADT was goserelin for 3 years, and androgen-receptor inhibitor for 3 weeks (to start)
413 patients were accrued between 2002-2006. The results of this study cohort have previously been published (Fizazi Eur J Cancer 2012, Fizazi Lancet Oncology 2015). However, it should be noted that 57-58% were Gleason 7, 59% were Gleason > 20, 29% were pN+, and 67% were pT3-T4. The two prior studies had already established the following:
1) It was the first study to test docetaxel in high-risk localized prostate cancer
2) Tolerated well – 2% neutropenic fever, no deaths
3) No negative impact on QOL at 1 year
4) PSA response improved (p < 0.001)
5) Relapse-free survival (RFS), which was primary endpoint, significantly improved (HR 0.71, p = 0.017) – at that time, median follow-up was 8 years
However, since that time, additional trials have reported on the use of doxetaxel in high-risk localized PCa with mixed results:
- STAMPEDE, RTOG 0521 support same findings – meta-analysis, HR 0.70, p < 0.001
- SPCG12, VA CSP #553, SPCG13 had contradictory findings
His following slide was important to this update.
In the original study, RFS included PSA relapse. But clinical RFS excludes PSA response. Each subsequent outcome is more selective.
In this follow-up, now with 12 years follow-up, they sequentially assessed RFS, cRFS and MFS. They only went to the next outcome if the first one was significant. They found the following:
- RFS – Median RFS 11.6 vs. 8.1 months (3.5 year benefit), HR 0.71, p = 0.01
- On subgroup analysis, this held up for pN+, PSA > 20, T3-4 disease – but also for patients with Gleason score < 7 interestingly
- cRFS – Median 13.9 months vs. 12.5 months, HR 0.75, p = 0.049
- MFS – HR 0.81 but p = 0.16. The curves appear to separate, but maybe not enough events. Technically not significantly different.
- Importantly, looking at second malignancies, there was no difference in the rate of second malignancy development (32 in each arm, ~15% each arm)
- CSS and OS (exploratory analyses) – no difference
1) Very long follow-up is needed to assess outcomes for high risk localized prostate cancer
2) 4 cycles of chemotherapy reduces the risk of clinical relapse or death
In the discussion period, Dr. Efstathiou made it a point to start off by congratulating the research team. She reminded everyone that when the study was started, docetaxel hadn’t even been established as a standard of care for metastatic prostate cancer. So, this trial was truly avant-garde, and they have demonstrated an impressive ability to follow these patients in the long-term.
First, the definition of high-risk localized PCa varies from study to study. But, regardless, patients with high-risk localized prostate cancer have mortality rates approaching men with pN+ and metastatic disease. In a healthy <65 year old man diagnosed with this, they have ~35% chance of prostate cancer mortality – but only 10% chance of other-cause mortality (including low rate of 2nd cancers as depicted in this study). Single-modality therapy is not sufficient!
Her main criticisms of the current study are:
1) Study design utilizes 4 cycles of docetaxel – which was appropriate at that time, but in today’s world, would have been 6 cycles.
2) <50% of the population had Gleason 8-10 disease – most had Gleason 7 disease, which may not meet criteria for the other studies.
However, she highlights the importance of looking at cRFS rather than just RFS (including PSA recurrence).
She also reviewed the other studies that have looked at and corroborated the use of docetaxel in this patient population – STAMPEDE and RTOG 0521. She spent a little bit of time highlighting some of the work her group has done looking at abiraterone in the same setting, in combination with radiotherapy – in an ASCO 2016 abstract, she had presented some early results of a neoadjuvant study. In that study, they found that abiraterone resulted in significant tumor volume reduction but now downgrading. With longer follow-up, they are close to reporting reduced RFS with abiraterone as well (p < 0.01).
Her take-home points from the discussion were:
1) From a therapeutics standpoint:
- cRFS are compelling and reinforcing to RFS data alone
- Given current data, comfortable with 6 cycles of neoadjuvant docetaxel – but for who?
2) From a clinical trial standpoint:
- This was an example of perseverance providing long-term data
While our current treatment paradigm for high-risk localized prostate cancer has not changed – it is close to changing!
Presented by: Karim Fizazi, MD, Ph.D., Medical Oncologist, Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France and Professor in Oncology at the University of Paris
Discussant: Eleni Efstathiou, MD, Ph.D., Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Houston, US
Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, twitter: @tchandra_uromd, @TjuUrology at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany