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Phase II randomized study of salvage radiation therapy plus enzalutamide or placebo for high-risk prostate-specific antigen recurrent prostate cancer after radical prostatectomy: the SALV-ENZA trial

  • Phuoc T. Tran,
  • Kathryn Lowe,
  • Hua-Ling Tsai,
  • Daniel Y. Song,
  • Arthur Y. Hung,
  • Jason W.D. Hearn,
  • Steven Miller,
  • James A. Proudfoot,
  • Matthew P. Deek,
  • Ryan Phillips,
  • Tamara Lotan,
  • Channing J. Paller,
  • Catherine H. Marshall,
  • Mark Markowski,
  • Shirl Dipasquale,
  • Samuel Denmeade,
  • Michael Carducci,
  • Mario Eisenberger,
  • Theodore L. DeWeese,
  • Matthew Orton,
  • Curtiland Deville,
  • Elai Davicioni,
  • Stanley L. Liauw,
  • Elisabeth I. Heath,
  • Stephen Greco,
  • Neil B. Desai,
  • Daniel E. Spratt,
  • Felix Feng,
  • Hao Wang,
  • Tomasz M. Beer,
  • Emmanuel S. Antonarakis

Publication: Journal of Clinical Oncology, November 2022

Purpose

We sought to investigate whether enzalutamide (ENZA), without concurrent androgen deprivation therapy, increases freedom from prostate-specific antigen (PSA) progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP).

Patients and methods

Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double‐blind, phase II, placebo-controlled, multicenter study of SRT plus ENZA or placebo (ClinicalTrials.gov identifier: NCT02203695). Random assignment (1:1) was stratified by center, surgical margin status (R0 v R1), PSA before salvage treatment (PSA ≥ 0.5 v < 0.5 ng/mL), and pathologic Gleason sum (7 v 8‐10). Patients were assigned to receive either ENZA 160 mg once daily or matching placebo for 6 months. After 2 months of study drug therapy, external-beam radiation (66.6‐70.2 Gy) was administered to the prostate bed (no pelvic nodes). The primary end point was FFPP in the intention-to-treat population. Secondary end points were time to local recurrence within the radiation field, metastasis‐free survival, and safety as determined by frequency and severity of adverse events.

Results

Eighty-six (86) patients were randomly assigned, with a median follow-up of 34 (range, 0-52) months. Trial arms were well balanced. The median pre-SRT PSA was 0.3 (range, 0.06-4.6) ng/mL, 56 of 86 patients (65%) had extraprostatic disease (pT3), 39 of 86 (45%) had a Gleason sum of 8-10, and 43 of 86 (50%) had positive surgical margins (R1). FFPP was significantly improved with ENZA versus placebo (hazard ratio [HR], 0.42; 95% CI, 0.19 to 0.92; P = .031), and 2-year FFPP was 84% versus 66%, respectively. Subgroup analyses demonstrated differential benefit of ENZA in men with pT3 (HR, 0.22; 95% CI, 0.07 to 0.69) versus pT2 disease (HR, 1.54; 95% CI, 0.43 to 5.47; Pinteraction = .019) and R1 (HR, 0.14; 95% CI, 0.03 to 0.64) versus R0 disease (HR, 1.00; 95% CI, 0.36 to 2.76; Pinteraction = .023). There were insufficient secondary end point events for analysis. The most common adverse events were grade 1-2 fatigue (65% ENZA v 53% placebo) and urinary frequency (40% ENZA v 49% placebo).

Conclusion

SRT plus ENZA monotherapy for 6 months in men with PSA-recurrent high-risk prostate cancer after RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time.

Commentary by Prof. Tsaur

Salvage radiotherapy (SRT) is considered a modern-day standard of care for patients with prostate cancer (PCa) experiencing biochemical relapse after radical prostatectomy (RP). While oncological outcomes were comparable, a higher urinary morbidity including urinary incontinence and urethral strictures after adjuvant as compared to early salvage radiotherapy was demonstrated in RADICALS-RT trial (1). Based on this and other evidence, early SRT is therefore a preferred management for biochemically recurrent (br) PCa in most males with PSA-relapse after RP except for those with particularly high-risk features that would probably benefit most from adjuvant RT.

Importantly, the addition of hormonal therapy to RT for the management of brPCa was supposed to potentiate its efficacy due to induced apoptosis and senescence as well as increased radio sensitisation of PCa cells by inhibition of DNA repair pathways. Indeed, the NRG/RTOG 96-01 and GETUG-016 trials yielded improved overall and progression-free survival, respectively, for combining RT with either bicalutamide 150 mg for 24 months or androgen deprivation therapy (ADT) for 6 months. (2, 3). However, a secondary analysis of the NRG/RTOG 96-01 trial showed that addition of long-term antiandrogen therapy to SRT in men with PSA ≤ 0.6 ng/ml did not yield a survival advantage but was conversely associated with an elevated risk for other-cause mortality as well as late grades 3 to 5 cardiac and neurologic toxic effects necessitating further tailoring of this combinational approach (4).   

Tran et al. enrolled men with a high-risk brPCa defined as a Gleason sum of 8-10 or Gleason 7 with either pT3 or R1 disease at RP into a randomised, double-blinded, phase II, placebo-controlled study to receive enzalutamide or placebo for 6 months. After 2 months of oral therapy, RT was performed. Staging consisted of CT-scan of the abdomen and 99Tc bone scan (or sodium fluoride PET scan). Biochemical relapse for study entry was defined as one rise in PSA ≥ 0.05 ng/ml, whereas absolute PSA level had to be < 0.7 ng/ml. The primary outcome measure was freedom from PSA progression (FFPP), which was determined as detectable PSA value ≥ 0.2 ng/ml with a second confirmatory PSA value of ≥ 0.4 ng/ml measured at least 8 weeks later for those individuals who achieved an undetectable on-study PSA value, otherwise it was defined as a 0.2 ng/ml elevation over nadir.

The study failed to achieve a predetermined accrual goal (96 participants, 39 PSA-progression events), so it was prematurely terminated. Assessment of the enrolled 86 patients with the follow-up time of 34 months yielded a 58% relative improvement in FFPP with addition of enzalutamide to SRT as compared to SRT alone. Subgroup analysis showed a benefit of the combination therapy for males with pT3 or R1 disease at RP. Most common adverse events grade 1-2 more frequently encountered on enzalutamide than on placebo was fatigue (65% vs. 53%, respectively), those of grade 3 were infrequent. Transcriptomic profiling analysis yielded promising results for ability of some gene expression signature subgroups, e.g. high Decipher score, ERG-positive status or PAM50 luminal subtype to predict for the greater relative benefit of enzalutamide over placebo. 

This is the first randomised trial assessing the addition of second-generation hormone therapy to SRT in brPCa after RP. It illustrates the promising potential of short-term enzalutamide to hinder PSA-progression when used concurrently to SRT. Keeping in mind that many PSA recurrences would never lead to more relevant oncological endpoints, a substantial limitation of the trial results is a low number of events (no local recurrences, one metastasis) precluding assessment of such crucial secondary end points as local recurrence within the radiation field or metastasis-free survival (MFS).

Importantly, a recent analysis of NRG Oncology/RTOG 9601 study data revealed that particularly MFS (but not FFPP) is a robust surrogate for overall survival in brPCa (5). Further restriction is that neither PSA doubling time was used in the trial for a better stratification of males with a high-risk brPCa who would probably benefit more from additional hormonal treatment nor PSMA-PET-CT was utilised to more precisely exclude distant recurrence. Nevertheless, the findings are hypothesis-generating for future research on identifying the optimal agent added for the optimal term hence further improving outcomes of SRT in brPCa.  

Reference:

  1. Parker CC, Clarke NW, Cook AD, Kynaston HG, Petersen PM, Catton C, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet. 2020;396(10260):1413-21.
  2. Carrie C, Magne N, Burban-Provost P, Sargos P, Latorzeff I, Lagrange JL, et al. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial. Lancet Oncol. 2019;20(12):1740-9.
  3. Shipley WU, Seiferheld W, Lukka HR, Major PP, Heney NM, Grignon DJ, et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017;376(5):417-28.
  4. Dess RT, Sun Y, Jackson WC, Jairath NK, Kishan AU, Wallington DG, et al. Association of presalvage radiotherapy PSA levels after prostatectomy with outcomes of long-term antiandrogen therapy in men with prostate cancer. JAMA Oncol. 2020;6(5):735-43.
  5. Jackson WC, Tang M, Schipper MJ, Sandler HM, Zumsteg ZS, Efstathiou JA, et al. Biochemical failure is not a surrogate end point for overall survival in recurrent prostate cancer: Analysis of NRG Oncology/RTOG 9601. J Clin Oncol. 2022;40(27):3172-9.