Prostate cancer remains a leading cause of cancer-related morbidity and mortality both in Ireland and worldwide. There is much research ongoing in the management of both early and locally advanced prostate cancer. There is also an ever-growing evidence base and experience in the management of men with metastatic prostate cancer. Prostate cancer management can be multimodality depending on the stage, and can include surgery, radiotherapy, androgen deprivation therapy (ADT), chemotherapy and stereotactic body radiotherapy (SBRT). These treatments can be used alone or in combination, depending on disease characteristics and the presence or absence of local or distant spread.

In the management of localised prostate cancer, one of the most important areas under investigation is the use of SBRT in the management of localised prostate cancer. The first toxicity data from the PACE B trial was presented at the American Society of Clinical Oncology annual conference earlier this year (ASCO 2019), showing similar genitourinary and gastrointestinal toxicity rates with SBRT as compared to hypofractionated external beam radiotherapy (EBRT). Hypofractionation refers to the use of doses of more than 2Gy per fraction.

The SPPORT trial, presented at American Society of Therapeutic Radiation Oncology annual meeting in October 2018 (ASTRO 2018), also looks at the management of localised prostate cancer but focuses on salvage radiotherapy post prostatectomy. It has provided further evidence for the use of ADT with salvage radiotherapy and for the first time has shown level 1 evidence of benefit (in terms of failure free survival) with the addition of elective pelvic lymph node radiotherapy (PLNRT). It suggests a benefit with the addition of PLNRT in patients with a pre-salvage PSA of > 0.35ng/ml.

There is also increasing evidence for the use of radiotherapy in the metastatic setting, both to the prostate and to metastases. This evidence is provided by the latest publication from the STAMPEDE group and in the recently published phase II SABR-COMET trial respectively. In addition there have also been recent publications exploring the use of novel antiandrogens in the management of hormone sensitive metastatic prostate cancer. These trials utilised two different agents – apalutamide in the Titan trial, and enzalutamide in the Enzamet trial. Both of these trials were positive, showing an improvement in overall survival (OS) and progression free survival (PFS) with the use of these agents before the development of castrate resistance. 

Further evidence is needed to guide combinations and sequencing of approaches. These trials will be discussed in greater detail below.

Localised prostate cancer

PACE

There is growing experience in the use of SBRT in the management of localised prostate cancer. Evidence to date has shown it to be safe and effective for this use. Currently, however, randomised phase III data to support this is lacking. It has already been established by a number of randomised phase III clinical trials that moderately hypofractionated external beam radiotherapy (MHRT) is non-inferior to conventionally fractionated EBRT in the management of localised prostate cancer. The next logical step is extreme or ultra hypofractionation in the form of SBRT, which has the benefit of fewer hospital attendances for patients and may also have an oncological advantage over EBRT and MHRT given the biology of prostate cancer. This question is being investigated in the international phase III PACE trial;¹ a two-arm trial comparing radical prostatectomy to SBRT (36.25Gy in five fractions) to the prostate in arm A, and SBRT to standard radiotherapy (either conventional fractionation [78Gy in 39 fractions] or moderately hypofractionated radiotherapy [62Gy in 20 fractions]) in arm B. Its primary objective is to assess whether hypofractionated SBRT offers therapeutic benefit over prostatectomy or conventional radiotherapy in men with early stage, organ-confined prostate cancer. This trial permits only patients with low or intermediate risk organ-confined prostate cancer (T1-T2, Gleason score ≤ 3 + 4, PSA ≤ 20ng/ml), and androgen deprivation therapy is not permitted. This trial was opened to recruitment in August 2012 and PACE A remains open, while recruitment in Pace B completed in January 2018. The first acute toxicity data from PACE B² was presented in abstract at ASCO in February 2019. According to a per protocol analysis, 430 patients received fractionated RT and 414 patients received SBRT. Key demographics across the two treatment arms of fractionated RT versus SBRT show mean age of 69.5 versus 69.3 years; T-stage ≥ T2b: 51.8% versus 56.6%; Gleason score 3 + 4: 80.2% versus 85.0% and PSA 10-20ng/ml: 30.9% versus 31.6%. Grade 2 or higher toxicity was not significantly different in the fractionated arm compared to the SBRT arm. G2 or higher genitourinary toxicity 27.2% versus 23.2%, p = 0.179. Acute grade 2 or higher gastrointestinal toxicity 12.1% versus 10.1% (p = 0.368) in the SBRT arm. 

It is promising to see that SBRT is tolerable in terms of acute toxicity. Outcomes are awaited regarding long-term toxicity and biochemical failure free survival. Follow up is ongoing.

SPPORT

The role for the use of salvage radiotherapy to the prostate bed in the setting of biochemical failure post radical prostatectomy has long been established. In recent years, trials have shown an improvement in biochemical failure free survival with the addition of ADT to salvage radiotherapy. Trials examining this include RTOG 9601³ and GETUG-AFU 16.⁴ There has not been any previous randomised phase III data to prove the benefit of elective pelvic lymph node radiotherapy in the salvage setting. An interim analysis of the NRG/RTOG 0534/SPPORT trial⁵ looking at ADT +/- pelvic lymph node radiotherapy in addition to salvage radiotherapy was presented in abstract at ASTRO 2018. Patients were randomised to one of three arms:

Arm 1 – prostate bed radiotherapy (PBRT) alone to a dose of 64.8Gy to 70.42Gy

Arm 2 – PBRT to the same dose with the addition of neoadjuvant and concurrent short-term androgen
deprivation (STAD) for four to six months

Arm 3 – PBRT to the same dose as arms 1 and 2, with STAD as per arm 2 with the addition of PLNRT to a dose of 45Gy in 25 fractions.

The primary endpoint of this trial is freedom from progression (FFP) at five years. FFP is defined as absence of biochemical failure by Phoenix criteria (PSA ≥ nadir PSA + 2ng/ml), clinical progression (local, regional or distant) or death due to any cause. Some 87% of patients received intensity-modulated radiotherapy (IMRT). The median dose delivered to the prostate bed was 68Gy. A total of 1,792 patients were recruited between February 2008 and February 2015. Baseline characteristics show median age of 64, seminal vesicle involvement in 14.8%, Gleason score < 8 in 83%, pre-radiotherapy PSA ≤ 1ng/ml in 89%, prostatectomy stage pT2 in 54.3% and positive surgical margins in 50.1% of cases. The median follow up was 5.4 years. The five-year FFP was 71% in arm 1 (PBRT alone), 81% in arm 2 (PBRT and STAD), and 89% in arm 3 (PLNRT, PBRT and STAD). The arms were then compared to one another with arm 3 versus arm 1 (p < 0.0001) revealing a HR of 0.45 (97.5% CI 0.34 to 0.61), arm 2 versus arm 1 (p < 0.0001), HR 0.62 (97.5% CI 0.47 to 0.82) and arm 3 versus arm 2 (p = 0.0039), HR 0.71 (97.5% CI 0.52 to 0.98). 

In a more in-depth analysis of the data, it is noted that in patients with a pre-radiotherapy PSA of < 0.34, there remained a statistically significant improvement in freedom from progression with PBRT with the addition of ADT compared with PBRT alone (arm 2 versus arm 1, p = 0.0002, HR 0.54) but not with the addition of PLNRT (arm 3 versus arm 2, p = 0.049, HR 0.32). In an analysis of patients with pre-radiotherapy PSA ≥ 0.34, there was a statistically significant benefit with the addition of PLNRT to PBRT and ADT (arm 3 versus 2, p = 0.17, HR 0.65, 97.5% CI 0.44 to 0.97). This suggests a pre-radiotherapy PSA level of 0.34 as a cut off level for those who will derive a benefit from the addition of PLNRT and a benefit of ADT in all patients regardless of PSA. Freedom from distant metastases at five years was not significantly different statistically between arms (arm 1 = 91.7%, arm 2 = 94.4%, arm 3 = 95.2%). There was no statistically significant difference in late grade 2+ or grade 3+ gastrointestinal or genitourinary side-effects between the three arms. The addition of PLNRT has shown an improvement of freedom from progression and follow up is ongoing to determine the magnitude of the benefit of addition of PLNRT, as well as the correlation between freedom from progression and clinical progression. Follow up is on-going and full trial publication is awaited.

Metastatic prostate cancer

There have been two recent trials published investigating the use of radiotherapy with a view to increasing overall survival in patients with metastatic prostate cancer. The latest publication from the STAMPEDE multi-arm multi-phase trial of patients with metastatic prostate cancer investigates treatment of the prostate with fractionated radiotherapy. The SABR-COMET trial investigates the treatment of metastatic lesions in patients with oligometastatic cancer (of prostate and other primary malignancies).

STAMPEDE

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase III trial⁶ by Parker et al was published in The Lancet in October 2018. This trial was designed to test the hypothesis that radiotherapy to the primary tumour would improve overall survival. Retrospective reviews of metastatic prostate cancer have also suggested an improvement in overall survival when treating the primary.^7,8,9,10 This trial was carried out at 117 institutions in Switzerland and the UK, where patients with newly diagnosed metastatic prostate cancer, without any previous radical treatment, were randomised to standard of care (lifelong ADT with or without upfront docetaxel) or to standard of care plus radiotherapy with a dose of 55Gy in 20 fractions over four weeks or 36Gy in six weekly fractions delivered to the prostate only. The primary outcome was overall survival. Between 2013 and 2016, 1,029 patients were randomised to the control arm and 1,032 to the radiotherapy arm. The metastatic burden was classified according to the definition used in the CHAARTED trial:¹¹ high metastatic burden was defined as four or more bone metastases with one or more outside the vertebral bodies or pelvis, or visceral metastases, or both; all other assessable patients were considered to have low metastatic burden. Metastases were determined with conventional imaging only (CT TAP and bone scan). Baseline characteristics were well balanced between arms. The median age of participants was 68, the median PSA pre-ADT commencement was 97ng/ml, and 79% of patients had a Gleason grade of 8 or higher. In the radiotherapy arm 89% of patients had a T stage of 3 or 4, 64% of patients were node positive and 43% had a low metastatic burden by the CHAARTED definition. Some 52% of patients were nominated to the daily radiotherapy schedule. Upfront docetaxel was administered to 18% of all patients (18% of patients in the control arm and 18% in the radiotherapy arm). In the published results, with a median follow up of 37 months, there was no survival benefit noted with radiotherapy (stratified log-rank test p = 0.451; HR 0.92, 95% CI 0.80 to 1.06; p = 0.266) for unselected patients. In the pre-specified subgroup analysis of overall survival subdivided by metastatic burden, overall survival was improved by radiotherapy in patients with low metastatic burden (HR 0.68, 95% CI 0.52 to 0.90; p = 0.007); with a three-year overall survival of 73% in the control arm versus 81% with radiotherapy. Conversely, there was no survival benefit in patients with a high metastatic burden (HR 1.07, 95% CI 0.90 to 1.28; p = 0.420). Adverse effects in the radiotherapy arm were modest, with 5% of patients reporting a highest grade 3 or 4 acute toxicity on the RTOG toxicity scale, 5% of patients had grade 3 or 4 acute bladder toxicity and 1% had an acute grade 3 or 4 bowel toxicity. There were no grade 5 toxicities. Rates of acute toxicity were slightly higher with daily compared to weekly fractionation. Only 1% of patients in the control arm and 4% of patients in the radiotherapy arm had a late grade 3 or 4 toxicity. 

The trial concludes that radiotherapy to the prostate improves survival in men with a low metastatic burden and should be the new standard of care, although the definition of low metastatic burden will likely need to be further clarified and caution should be used with advanced imaging such as PET CT, which may lead to upstaging of more patients and some patients missing out on the potential benefit of radiotherapy. 

The optimum dose schedule and the potential role of metastases directed therapy remain unclear (ie. SBRT) as well as the role of the addition of abiraterone, which has been shown by James et al¹² to improve overall survival and failure free progression in metastatic prostate cancer in the absence of radiotherapy.

SABR-COMET

The SABR-COMET¹³ trial was a randomised, open label phase II trial carried out at 10 hospitals in Canada, the Netherlands, Scotland and Australia, published in The Lancet in May 2019. It was designed to assess in a randomised trial the effect on overall survival of stereotactic ablative radiotherapy (SABR) on patients with a controlled primary malignancy and oligometastatic disease (defined as one to five metastases, with no more than three in any one organ). Patients had to have had their primary tumours treated at least three months previously with no progression at the primary site. SABR involves the use of very high dose per treatment radiation therapy and highly conformal radiotherapy planning techniques. Exclusion criteria in this trial included metastasis to a femoral bone, three or fewer brain metastases, previous radiotherapy to a site requiring SABR and tumour within 3mm of the spinal cord. Patients were required to have a life expectancy of at least six months, as judged by the enrolling physician. Patients were randomised in a 1:2 ratio to standard of care treatment (which could include palliative radiotherapy) or standard of care plus SABR to all metastases. Between February 2012 and August 2016, 33 patients were randomised to the control arm and 66 to the SABR arm. In the SABR arm, the single most common primary site of original tumour was prostate, accounting for 21% of cases, followed by breast (20%), lung (18%), colorectal (14%) and other sites constituted 27%. Before enrolment, 48% of patients in the control group and 45% of patients in the SABR group underwent PET­ CT. Very few patients had the maximum five permitted metastases (5% of the SABR arm and 0% of the control arm). Some 75% of patients in the SABR arm had one or two metastases only. The most common location of metastases in the SABR arm was lung (43%), followed by bone (35%), liver (13%), adrenal (6%) and other (3%). This trail utilises a randomised phase II screening design with a two-sided alpha of 0.20, whereby p < 0.20 signifies a positive trial. With a median follow up of 25 months in the control arm and 26 months in the SABR arm, the primary outcome, death from any cause, occurred in 48% of patients in the control group and 36% of patients in the SABR group. Median overall survival was 28 months (95% CI 19 to 33) in the control group versus 41 months (26-not reached) in the SABR group (HR 0.57, 95% CI 0.30 to 1.10; stratified log-rank p = 0.090).¹⁵ Disease progression occurred in 59% of patients in the SABR group compared to 85% of patients in the control group. Median PFS was six months (95% CI 3.4 to 7.1) in the control group versus 12 months (6.9 to 30.4) in the SABR group (HR 0.47, 95% CI 0.30 to 0.76; stratified log-rank p = 0.0012). This benefit in overall and progression free survival came at the cost of increased toxicity. Grade 2 or higher adverse events occurred in 9% of patients in the control group, compared to 29% of patients in the SABR group (p = 0.026). Unfortunately, there were three (4.5% of patients) treatment-related deaths in the SABR group. In this phase II trial there is a significant improvement in OS and PFS, albeit at the cost of greater toxicity. However, phase III trials will be required to definitively show a benefit and define the maximum number of metastases in which SABR is beneficial. There are two follow on phase III trials proposed, SABR-COMET 3 (controlled primary and one to three metastases) and SABR-COMET 10 (controlled primary and four to 10 metastatic lesions).

TITAN and ENZAMET

There have been two trials of systemic therapy with androgen receptor inhibitors in hormone sensitive metastatic prostate cancer published in the New England Journal of Medicine in July 2019: the Titan¹⁴ trial in May 2019 and the Enzamet¹⁵ trial in June 2019. The Enzamet trial was an open label randomised phase III trial in which 1,125 patients were randomised to receive either enzalutamide 160mg daily or a standard nonsteroidal antiandrogen drug (bicalutamide, nilutamide or flutamide) to assess if there was a delay to castrate resistance and an improvement in overall survival. Both groups received standard of care with ‘continuous testosterone suppression’. High volume metastatic disease was present in 52% of patients in each group. Early planned docetaxel was permitted in both groups, with the full six cycles being administered to 65% of patients in the enzalutamide group and 76% of patients in the standard care group. At the time of analysis, with a median follow up of 34 months, median overall was not reached in either group. 

There were, however, 102 deaths in the enzalutamide group and 143 deaths in the standard care group (HR for death, 0.67; 95% CI 0.52 to 0.86; p = 0.002). The overall survival at three years is estimated at 80% in the enzalutamide arm compared to 72% in the standard arm. There was a more significant effect on progression free survival with a rate of 67% in the experimental arm compared to 37% in the standard arm (HR, 0.39; 95% CI, 0.33 to 0.47; < 0.001). This trial concludes that the early addition of enzalutamide improves OS, as well as prostate-specific antigen (PSA) and clinical PFS within three years, however it comes at the expense of increased fatigue and seizures. 

The Titan trial used a different novel anti-androgen (apalutamide) in a similar population; men with hormone-sensitive metastatic prostate cancer. This trial was a randomised double blind phase III trial in which 525 men were randomised to receive apalutamide 240mg once daily, and 527 randomised to placebo; in addition to standard of care with ADT in the form of a gonado-tropin-releasing hormone (GnRH) agonist or antagonist in both groups. The primary end points were radiographic progression free survival and overall survival. Patients were permitted to have previously received docetaxel but did not receive early planned docetaxel during the trial. In the apalutamide arm, 11% of patients previously received docetaxel, compared to 10.4% of patients in the placebo arm. Some 61.9% of patients in the experimental arm and 63.9% in the standard arm had high volume metastatic disease. At 24 months, 68.2% of patients in the apalutamide group had radiographic PFS compared to 47.5% of patients in the standard group, with a hazard ratio for radiographic progression or death of 0.48; 95% CI, 0.39 to 0.60; p < 0.001). The benefit of apalutamide was consistent across subgroups including high and low volume metastatic disease. 

The overall survival at 24 months was 82.4% in the apalutamide group and 73.5% in the placebo group (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; p = 0.005), and there was a 33% lower risk of death in the apalutamide group. This benefit was not affected by disease volume. Apalutamide was well tolerated without significant differences in grade 3+ or serious adverse events between arms. Apalutamide and enzalutamide are now proven in phase III randomised controlled trials to improve overall and progression free survival in this group of patients with castrate sensitive metastatic prostate cancer. These results also support their early use in newly diagnosed metastatic prostate cancer.

Conclusion

The trials discussed here provide further high level evidence to assist physicians in managing prostate cancer, whether in the localised or metastatic setting. Particularly in the metastatic setting, not only are new systemic agents showing benefit in terms of overall and progression free survival in castrate-sensitive patients, new evidence-based indications are also emerging for the use of radiotherapy to the primary tumour and oligometastases. 

Further randomised data will be required to determine the true benefit of metastasis-directed treatment in prostate cancer and data is still awaited on the combination of radiotherapy to the primary tumour, as well as the treatment of metastases with SBRT. In addition, the optimum integration and/or sequencing of this approach with systemic agents that are known to improve overall survival in low metastatic burden prostate cancer have yet to be determined. 

An important caveat is that the STAMPEDE trial did not utilise PSMA PET-CT for staging and less than half of the patients in the SABR-COMET trial population had a PET pre-treatment. This could alter management strategies in future as this imaging technique becomes more readily available.

References

1. Morrison K, Tree A, Khoo V, Van As N. The PACE trial: International randomised study of laparoscopic prostatectomy vs. stereotactic body radiotherapy (SBRT) and standard radiotherapy vs. SBRT for early stage organ-confined prostate cancer. J Clin Oncol 2018; 36(6_suppl):TPS153-TPS153
2. Van As N, Brand D, Tree A et al. PACE: Analysis of acute toxicity in PACE-B, an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (CFMHRT) for localized prostate cancer (LPCa). J Clin Oncol 2019; 37 (7_suppl):1-1
3. Shipley W, Seiferheld W, Lukka H et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Eng J Med 2017; 376(5):417-28
4. Carrie C, Hasbini A, de Laroche G et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. The Lancet Oncology 2016; 17(6):747-56
5. Pollock A. Short term androgen deprivation therapy with or without pelvic lymph node treatment added to prostate bed only salvage radiotherapy: The NRG/RTOG 0534/SPPORT trial. In: Proceedings of the 60th Annual Meeting of the American Society for Therapeutic Radiation Oncology 2018 Oct 21-28; San Antonio. Texas (TX). ASTRO 2018. Abstract NR LBA 5
6. Parker C et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. The Lancet 2018; 392(10162):2353-66
7. Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014; 65:1058-66
8. Fossati N, Trinh QD, Sammon J et al. Identifying optimal candidates for local treatment of the primary tumor among patients diagnosed with metastatic prostate cancer: a SEER-based study. Eur Urol 2015; 67:3-6
9. Gratzke C, Engel J, Stief CG. Role of radical prostatectomy in metastatic prostate cancer: data from the Munich Cancer Registry. Eur Urol 2014; 66:602-03
10. Rusthoven CG et al. Improved survival with prostate radiation in addition to androgen deprivation therapy for men with newly diagnosed metastatic prostate cancer. J Clin Oncol 2016; 34:2835-42
11. Sweeney CJ et al. Chemohormonal therapy in metastatic hormone sensitive prostate cancer. N Engl J Med 2015; 373:737-46
12. James N, de Bono J, Spears M et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Eng J Med 2017; 377(4):338-351
13. Palma D, Olson R, Harrow S et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. The Lancet. 2019; 393(10185):2051-8
14. Chi K, Agarwal N, Bjartell A et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Eng J of Med 2019; 381(1):13-24
15. Davis I et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Eng J Med 2019; 381(2):121-31