The first study to be presented was HORRAD.1 This was first presented at AUA 2018. In the prospective HORRAD trial, androgen deprivation therapy (ADT) with concurrent radiotherapy was compared to ADT alone in patients with primary bone metastases. This trial demonstrated no difference in the median survival, with 45 months in the radiotherapy group vs. 43 months in the control group, with a hazard ratio of 0.90, p =0.356. However, it should be noted that the patients included in this trial had primarily high volume disease – 67% had more than 5 bone metastases, median PSA at diagnosis was 125. Radiation doses were also given at slightly lower levels than currently given – 70 Gy in 35 fractions or 57.76 Gy in 19 fractions. Therefore, they were not exactly representative of the ideal oligometastatic patients. Furthermore, the selection of these patients was based solely on a bone scan – and there is no data on the status of the lymph nodes or visceral metastasis.
In a subgroup analysis of patients with PSA less than the median of 142 ng/mL, Gleason score <= 8, and less than five osseous metastases – no difference was shown in the overall survival. However, there was a separation of the Kaplan Meyer curves at two years follow-up, suggesting that with longer follow-up, a significant difference could be apparent.
This then leads to the STAMPEDE study, specifically the comparison of ADT+radiation to ADT alone.2 This was first presented at ESMO 2018. The basic study design was a 1:1 randomized trial comparing ADT (+/- docetaxel at the physician’s discretion) vs. ADT + prostate radiotherapy (+/- docetaxel at the physician’s discretion) – the radiotherapy was administered as 36 Gy/6 fractions/6 weeks or 55Gy/20 fractions/4 weeks (weekly vs. daily). Ultimately, 2061 patients were randomized – 1029 to SOC and 1032 to SOC+Radiation therapy. There was high metastatic burden in 58% of patients - 89% had bone mets and median PSA was 97. Yet, they had enough patients to stratify patients (post-hoc) into low and high volume disease (based on CHAARTED criteria). Ignoring volume of disease, similar to HORRAD, there was no survival advantage with adding radiotherapy. However, they identified that men with the low-volume metastatic burden (based on CHAARTED criteria) had significantly better PFS, MFS and OS than men with a higher metastatic burden. Specifically, OS was better in men treated with radiation who had low volume metastases (HR 0.68, p = 0.007). This has established radiation as a viable treatment option in this setting.
STOPCAP3 is a systematic review and meta-analysis that looks at all trials comparing radiotherapy + ADT vs. ADT alone, and includes the two studies mentioned above. It also mentions the PEACE-1 trial (ongoing), but these results were naturally not yet available. On pooled analysis of the above two trials (2126 men; 90% of those eligible) showed no overall improvement in survival or PFS with prostate radiotherapy. They did note that the effect of prostate radiotherapy varied by metastatic burden – and that there was 7% improvement in 3-yr survival in men with fewer than five bone metastases.
Knowing where we are now, some questions the discussants raised (and the brief talking points) are below:
1) Did patients in the RT arms receive adequate doses?
As mentioned above, current RT doses for primary radiotherapy range between 76-80 Gy, so these are both below current standards. It would suggest, however, that at higher doses, there may be an additional benefit – but this requires further evaluation.
2) Can we translate these findings to the surgical setting?
Some would argue that we can. The benefit likely likes in the local control of the disease. However, as Dr. Supiot mentioned, in men with advanced prostate cancer, a significant proportion of harbor DNA repair defects – and radiotherapy may yield benefit in these patients that would not be obtained by surgery alone.
Regardless, at this time, surgery cannot be recommended off clinical trial. However, there are a few clinical trials ongoing to address this very question and will be quite informative.
3) Should we consider concomitant metastases-direct therapy (MDT)?
Interestingly, none of these studies directly allowed for MDT – either with surgery or radiation. Yet, work by Ost et al. in the STOMP trial,4 MDT appears to at least delay need for systemic therapy and may add value in terms of survival. So, combining primary treatment of the prostate and MDT is the next step, and there are some ongoing GETUG trials that are addressing this.
4) Is the follow-up adequate?
The follow-up is shorter than the median survival – suggesting that longer follow-up may yield different results.
5) Can we rely on subgroup analyses?
The STAMPEDE data and HORRAD data regarding low-volume disease are both post-hoc subgroup analyses – and so the study isn’t powered to answer that question. Additional studies with a priori disease burden stratification may be needed to confirm these effects.
6) Does ADT alone still represent the SOC?
This is an important question, as the cM1 hormone-sensitive prostate cancer disease space has now changed. Both docetaxel and abiraterone are now approved in these patients and represent the new standard of care. Yet, primary treatment has not yet been compared to these combination treatments.
The two speakers provided a brief overview of an important topic and raised some important questions that we should be thinking about. This concept of oligometastatic prostate cancer continues to evolve, along with new novel staging studies (PET/CT). Therefore, as more data rolls in, more questions will arise.
Presented by: Giorgio Gandaglia, Department of Urology, Vita-Salute San Raffaele University, Milan, Italy
Discussant: Stéphane Supiot, Radiation Oncologist, University of Nantes, St Herblain, France
Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @TjuUrology) at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona, Spain, March 15-19, 2019.
References:
- Boeve LMS et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019 Mar;75(3):410-418. doi: 10.1016/j.eururo.2018.09.008. Epub 2018 Sep 25.
- Parker CC. et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018 Dec 1;392(10162):2353-2366. doi: 10.1016/S0140-6736(18)32486-3. Epub 2018 Oct 21.
- Burdett S et al. Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol. 2019 Feb 27. pii: S0302-2838(19)30111-3. doi: 10.1016/j.eururo.2019.02.003. [Epub ahead of print]
- Ost P et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial
DOI: 10.1200/JCO.2017.75.4853 Journal of Clinical Oncology 36, no. 5 (February 10 2018) 446-453.