Expert dissects recent research on radiation therapy for prostate cancer

Although radiation therapy has been a long-standing cancer treatment, questions remain about its use in prostate cancer, according to Anthony D’Amico, MD, PhD.

Anthony V. D’Amico, MD, PhD

Dana-Farber Cancer Institute

D’Amico, professor of radiation oncology at Harvard Medical School and chief of genitourinary radiation oncology at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute in Boston, Massachusetts, discussed recent research and current practice concerning the radiotherapeutic management of prostate cancer during a presentation to the 16th Annual Interdisciplinary Congress on Prostate Cancer® and Other Genitourinary Malignancies, hosted by Physicians’ Education Resource®, LLC (PER®).

In particular, he spoke about the effectiveness of various agents used in the treatment of prostate cancer in combination with radiation therapy, the choice between standard fractionation and hypofractionation and the optimal use of radiation therapy after surgery in adjuvant and salvage settings.

Hormone therapy for intermediate risk diseases

D’Amico first highlighted results from the Phase 3 RTOG 0815 trial (NCT00936390) which found that adding androgen deprivation therapy (ADT) to radiation therapy resulted in a reduction in the rate of metastases, a reduction in cancer-related deaths and a decrease in the frequency of prostate-specific antigen. (PSA) in patients with intermediate-risk prostate cancer.¹ In the radiotherapy alone and experimental arms, 125 and 68 patients, respectively, experienced PSA failure (HR, 0.52; 95% CI, 0.39-0.70; P < 0.001), 28 and 7 developed distant metastases (RR, 0.25; 95% CI, 0.11-0.57; P < 0.001), and 10 and 1 experienced a cancer-related death (HR. 0.10; 95% CI, 0.01-0.80; P = 0.007), respectively.

Additionally, D’Amico noted that previous data from the Phase 3 trials EORTC 22991 (NCT00021450) and GETUG 14 (NCT00104741) suggested that ADT delays progression.^2.3 Together, these 3 studies support the use of hormone therapy in combination with radiotherapy in patients at intermediate risk.

Hypofractionation

D’Amico then reviewed the current evidence regarding the dosage and timing of radiotherapy. He focused on recent findings from the Phase 3 CHHiP trial (ISRCTN97182923), which demonstrated the non-inferiority of hypofractionation compared to standard fractionation.⁴ However, these data also showed that hypofractionation caused a slight increase in late genitourinary toxicities. Therefore, D’Amico recommended careful patient selection for this dosing regimen to minimize these safety concerns.

Additionally, he added, ultra-hypofractionation was not inferior to conventional fractionation in the Phase 3 HYPO-RT-PC study (ISRCTN45905321), yielding failure-free survival similar to the conventional regimen, more frequent early adverse effects (AEs), and similar late toxicities in patients with intermediate to high risk prostate cancer.⁵

Agents for high-risk diseases

Regarding patients with high-risk disease, D’Amico first discussed the Phase 3 STAMPEDE trial (NCT00268476) examining ADT with or without abiraterone (Zytiga), which supported the regimen of abiraterone.⁶ A five-year follow-up showed a median survival of 46 months (interquartile range [IQR]25-92) in the ADT alone group vs 79 months (IQR 33-not reached [NR]) in the abiraterone group. The corresponding 5-year survival rates were 41% (95% CI, 37% to 45%) and 60% (95% CI, 50% to 71%), respectively.

He went on to note that docetaxel, although not supported by previous studies, may reduce prostate cancer-specific mortality in patients with PSA levels below 4 ng/mL, although these data are confounding. hypotheses.⁷ This study looked at docetaxel in combination with ADT and radiation therapy.

Post-operative radiotherapy

D’Amico concluded with a discussion of the value of adjuvant radiation therapy versus salvage radiation therapy.

The phase 3 RADICALS-RT study (NCT00541047) evaluated the timing of radiation therapy in 1396 patients and found similar results in the adjuvant and salvage arms.⁸ The 5-year biochemical progression-free survival (PFS) rate was 85% in the adjuvant group versus 88% in the salvage group (HR, 1.10; 95% CI, 0.81-1.49; P = 0.56). The proportion of patients without off-protocol hormone therapy was 93% in the adjuvant group and 92% in the salvage group (HR, 0.88; 95% CI, 0.58-1.33; P = 0.53).

The smaller GETUG-AFU 17 phase 3 trial (NCT00667069) also found no benefit of adjuvant radiotherapy over salvage radiotherapy in terms of event-free survival.⁹ The phase 3 RAVES trial (NCT00860652) failed to prove non-inferiority of salvage versus adjuvant radiotherapy.^ten

However, D’Amico noted that these 3 trials may have missed a possible benefit of adjuvant therapy in patients with adverse pathology at the time of surgery. To this end, a recent retrospective cohort study examined the effectiveness of radiation therapy in the adjuvant setting for patients with disease extending beyond the prostate as well as a Gleason score of 8 to 10. or positive pelvic lymph nodes.¹¹ The results suggested some clinical benefit to adjuvant radiotherapy, which carried a significantly lower risk of all-cause mortality than salvage radiotherapy, both when patients with positive lymph nodes were excluded (HR, 0, 33, 95% CI, 0.13-0.85; P = 0.02) and included (HR, 0.66; 95% CI, 0.44-0.99; P= 0.04).

D’Amico suggested that future randomized clinical trials should take these data into account in their design, in order to thoroughly test this difference in results. Accurate trial design will be crucial to improving the specificity of the data and allowing doctors to better tailor treatments to each patient, he concluded.

The references

1. Krauss DJ, Karrison TG, Martinez AA, et al. Increased-dose radiotherapy alone or in combination with short-term androgen suppression for intermediate-risk prostate cancer: results from the NRG Oncology/RTOG 0815 randomized trial. Int J Radia Oncol Biol Phys. 2021;111(supplement 3):S1. doi:10.1016/j.ijrobp.2021.07.039
2. Bolla M, Neven A, Maingon P, et al; EORTC Radiation Oncology Group. Short androgen suppression and increased radiation dose in prostate cancer: 12-year results from the EORTC 22991 trial in patients with localized disease at intermediate risk. J Clin Oncol. 2021;39(27):3022-3033. doi:10.1200/JCO.21.00855
3. Dubray BM, Salleron J, Guérif SG, et al. Is short-term androgen depletion added to high-dose radiotherapy (80 Gy) in localized intermediate-risk prostate cancer? Final analysis of the GETUG 14 randomized trial (EU-20503/NCT00104741). J Clin Oncol. 2016;34(supplement 15):5021. doi:10.1200/JCO.2016.34.15_suppl.5021
4. Syndikus I, Griffin C, Philipps L. Efficacy and comorbidity results over 10 years from a randomized phase III trial of conventional radiation therapy versus hypofractionated high-dose modulated radiation therapy for prostate cancer (CHHiP; CRUK/06/016). J Clin Oncol. 2023;41(supplement 6):304. doi:10.1200/JCO.2023.41.6_suppl.304
5. Widmark A, Gunnlaugsson A, Beckman L, et al. Ultra-hypofractionated versus conventional radiotherapy for prostate cancer: 5-year results of the randomized phase 3 HYPO-RT-PC non-inferiority trial. Lancet. 2019;394(10196):385-395. doi:10.1016/S0140-6736(19)31131-6
6. James ND, Clarke NW, Cook A, et al; STAMPEDE Trials Collaborative Group. Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the randomized STAMPEDE trial (NCT00268476). Int J Cancer. 2022;151(3):422-434. doi:10.1002/ijc.34018
7. D’Amico AV, Xie W, McMahon E, et al. Radiotherapy and androgen suppression therapy with or without docetaxel in the management of non-metastatic unfavorable risk prostate cancer: a prospective randomized trial. J Clin Oncol. 2021;39(26):2938-2947. doi:10.1200/JCO.21.00596
8. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): randomized controlled phase 3 trial. Lancet. 2020;396(10260):1413-1421. doi:10.1016/S0140-6736(20)31553-1
9. Sargos P, Chabaud S, Latorzeff I, et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen suppression therapy in men with localized prostate cancer after radical prostatectomy (GETUG-AFU 17): randomized phase 3 trial. Lancet Oncol. 2020;21(10):1341-1352. doi:10.1016/S1470-2045(20)30454-X
10. Kneebone A, Fraser-Browne C, Duchesne GM, et al. Adjuvant radiotherapy versus early salvage radiotherapy after radical prostatectomy (TROG 08.03/ANZUP RAVES): randomised, controlled, phase 3, non-inferiority trial. Lancet Oncol. 2020;21(10):1331-1340. doi:10.1016/S1470-2045(20)30456-3
11. Tilki D, Chen MH, Wu J, et al. Adjuvant radiotherapy versus early salvage radiotherapy for men at high risk of recurrence following radical prostatectomy for prostate cancer and risk of death. J Clin Oncol. 2021;39(20):2284-2293. doi:10.1200/JCO.20.03714