Neoadjuvant Systemic Therapy for Prostate Cancer: If a PUNCH Is Good, What Will It Take to Score a Knockout?

With all the randomized trial data supporting a survival benefit of androgen deprivation therapy with primary radiation to the prostate, it is unfortunate that the same results have not been achieved in combination with radical prostatectomy. The data has been replicated in multiple randomized controlled trials, confirming that addition of androgen deprivation therapy in a neoadjuvant, concurrent and adjuvant fashion to definitive primary local radiation leads to a survival benefit for men with high-risk prostate cancer.

Similar attempts have not to led to success when androgen deprivation therapy is combined with radical prostatectomy.2-4 These results with surgery were extremely disappointing to the field, recognizing the risk of distant recurrence in a man with high-risk localized prostate cancer is significant. Hence, other trials with aggressive combination therapies have been attempted.

One such recently reported trial, termed the PUNCH (CALGB now ALLIANCE 90203) trial, was presented at the American Urological Association meeting in 2019 with an update at the 20th Annual Meeting of the Society of Urologic Oncology later in the year. This trial randomized patients with high-risk localized prostate cancer to neoadjuvant chemohormonal therapy with radical prostatectomy to radical prostatectomy alone. Given the survival benefit seen with docetaxel combined with androgen deprivation therapy in the metastatic castration-sensitive prostate cancer setting in both the CHAARTED and STAMPEDE trials,5, 6 it seemed very logical that the same result might be seen when imported into the localized disease setting.

The PUNCH trial enrolled patients with cT1-3a, prostate-specific antigen (PSA) < or = 100 ng/mL, no evidence of radiographic metastases, and either Gleason 8-10 disease or Kattan pre-operative nomogram probability of <60% biochemical progression-free survival 5 years after radical prostatectomy. All patients received either six cycles of docetaxel with androgen deprivation therapy followed by radical prostatectomy with extended lymph node dissection or radical prostatectomy with extended lymph node dissection alone. The primary endpoint was 3-year biochemical progression-free survival (PFS), defined as PSA >0.2 ng/mL X 2 at least three months apart.

The study results were interesting and are certainly sparking much discussion. Although the primary endpoint of a landmark 3-year biochemical PFS was not statistically significant (hazard ratio [HR] 0.87 vs 0.82; p = 0.13), the overall analysis for biochemical PFS was statistically significant yielding an HR = 0.66; 95% confidence interval [CI]: 0.47-0.94; p<0.001.7 Overall survival (HR = 0.67; 95% CI: 0.43-1.06) was also in favor of the neoadjuvant therapy arm, although not meeting statistical significance. These findings emphasize the fact that the primary endpoint of biochemical progression-free survival as a landmark at three years, may not have been the ideal choice. Hence, more studies may need to be performed to demonstrate definitive benefit to neoadjuvant androgen deprivation therapy plus docetaxel for men with high-risk localized prostate cancer prior to radical prostatectomy.  Regardless, activity of the combination is established, and these results may end up falling victim to clinical trial design.

When uncertain, the default, in my opinion, is to continue to perform research aggressively. Therefore, the field is still open for novel neoadjuvant trial design and patient accrual. Below, I emphasize some neoadjuvant trials, prior to radical prostatectomy, that are actively accruing, and that may offer important insights in our attempts to cure more patients with high-risk localized prostate cancer.

Ongoing neoadjuvant systemic therapy prostate cancer trials for patients with high-risk disease:

  • Chemohormonal therapy (NCT04220398)
  • Niraparib for patients with DNA damage response defects (NCT04030559)
  • Aspirin and rintatolimod +/- interferon-alpha 2b (NCT03899987)
  • Dupilumab (NCT03886493)
  • Androgen deprivation therapy + enzalutamide + abiraterone using multiparametric MRI and 18FDCFPyL PET/CT (NCT03860987)
  • Atezolizumab +/- enzalutamide (NCT03821246)
  • Pembrolizumab + enzalutamide (NCT03753243)
  • Sulforaphane/broccoli sprout extract (NCT03665922)
  • Intratumoral or intramuscular PolylCLC (NCT03262103)
  • Degarelix +/- apalutamide (NCT03080116)
  • PROSTVAC + nivolumab (NCT02933255)
  • Apalutamide + Leuprolide (NCT02770391)
  • Ibrutinib (NCT02643667)
  • Leuprolide with abiraterone +/- cabazitaxel (NCT02543255)

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine, Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

References:

1. Bolla, Michel, Dionisio Gonzalez, Padraig Warde, Jean Bernard Dubois, René-Olivier Mirimanoff, Guy Storme, Jacques Bernier et al. "Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin." New England Journal of Medicine 337, no. 5 (1997): 295-300.

2. Soloway, Mark S., Kapil Pareek, Rooholiah Sharifi, Zev Wajsman, D. A. V. I. D. McLEOD, David P. Wood, Antonio Puras-Baez, and LUPRON DEPOT NEOADJUVANT PROSTATE CANCER STUDY GROUP†. "Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results." The Journal of urology 167, no. 1 (2002): 112-116.

3. van der Kwast, Theodorus H., Bernard Têtu, Bernard Candas, Jose-Luis Gomez, Leonello Cusan, and Fernand Labrie. "Prolonged neoadjuvant combined androgen blockade leads to a further reduction of prostatic tumor volume: three versus six months of endocrine therapy." Urology 53, no. 3 (1999): 523-529.

4. GLEAVE, MARTIN E., S. LARRY GOLDENBERG, JOSEPH L. CHIN, JOHN WARNER, FRED SAAD, LAURENCE H. KLOTZ, MICHAEL JEWETT et al. "Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects." The Journal of urology 166, no. 2 (2001): 500-507.

5. Sweeney, Christopher J., Yu-Hui Chen, Michael Carducci, Glenn Liu, David F. Jarrard, Mario Eisenberger, Yu-Ning Wong et al. "Chemohormonal therapy in metastatic hormone-sensitive prostate cancer." New England Journal of Medicine 373, no. 8 (2015): 737-746.

6. James, Nicholas D., Matthew R. Sydes, Noel W. Clarke, Malcolm D. Mason, David P. Dearnaley, Melissa R. Spears, Alastair WS Ritchie et al. "Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial." The Lancet 387, no. 10024 (2016): 1163-1177.

7. Eastham JA et al. AUA 2019; LBA12.