2. UroToday Home
  3. Clinical Trials
  4. From the Editor
Back to From the Editor Articles    

Metastatic Castration-Sensitive Prostate Cancer, What is Left to Do? A Lot!

Metastatic castration-sensitive prostate cancer (mCSPC) is a disease state that has grown in complexity, with arguably some of the greatest gains in our field of genitourinary oncology. That’s because the benefits of treatment intensification are indisputable with outstanding clinical trial hazard ratios and large median overall survival benefits. To briefly summarize, androgen receptor pathway inhibitors (ARPI) offer overall survival benefits when added to conventional androgen deprivation therapy (ADT). These benefits extend to abiraterone acetate,1,2 enzalutamide,3,4 and apalutamide.5 Docetaxel chemotherapy offers survival benefit for patients with high volume disease,6 and either abiraterone7 or darolutamide8 offer survival benefits when added to ADT and docetaxel for patients with de novo and high-volume mCSPC. There is also supportive data for low volume prostate cancer to apply prostate directed radiation for survival benefit from a subgroup analysis of the STAMPEDE trial.9

I’ve written a Clinical Trials Portal article on this disease state every couple of years, and the ongoing clinical trial landscape keeps aggressively changing.10-12 One would think that with so many advances for this disease state, that trial design would be challenging, with highly effective controls. However, there are still opportunities to design trials that satisfy unique niches. Over the next 6-12 months, I will highlight many of these niches. A few topics that come to mind are driven by strong patient interest, such as the use of immunotherapy or earlier incorporation of PSMA targeted radioligand therapy. Another opportunity is to design biomarker driven trials, using either molecular or clinical subtyping. An example would be the study of patients who harbor DNA repair gene mutations or those with aggressive molecular characteristics like p53, pTEN, and/or RB alterations. Finally, there are opportunities to improve patient quality of life through treatment deintensification trials or the use of agents that may harbor less toxicity. This leads to the obvious question that the field has: “Is docetaxel still necessary?” This is because the “triple therapy” trials that have been performed all used ADT with docetaxel in the control arm. We know that the ARPI clearly adds survival benefit, but is docetaxel still beneficial for our patients? Our field needs to test whether the addition of docetaxel to ADT with ARPI offers significant survival benefit.

To kick off the series, I will start by highlighting trials in this article that accrue broad populations and are actively accruing patients in the randomized phase 3 setting. Each of the concepts below warrant investigation and have promise to enter the treatment paradigm. For example, PTEN is not infrequently lost in prostate cancer,13 leading to constitutive activation of the PI3kinase pathway. Inhibiting downstream AKT is very rationale in that situation and worth exploring in clinical trials. Another approach is to inhibit CDK4/6, which inactivates the CCND-CDK4/6 complexes. This results in increased activity of phosphorylated Rb proteins, G1 arrest, and eventual apoptosis.14,15 As a result, use of a CDK/6 inhibitor should occur in earlier prostate cancer disease states, as treatment-resistant prostate cancer harbors more Rb inactivation.16 Finally, 177Lu-PSMA-617 has already shown, in the VISION trial, overall survival benefit in the post-ARPI and post-docetaxel population.17 PSMAfore has shown progression free survival benefit in the docetaxel-naïve metastatic castration-resistant prostate cancer population as well.18 It is natural to see whether those benefits extend earlier to the mCSPC population.

Below, I highlight ongoing, actively accruing, randomized, phase 3 trials for mCSPC. These are the trials that have the potential to introduce new agents to this earlier disease state where many victories have already recently been declared. Yet, there is nothing wrong with continuing to accumulate more wins for our patients!

Highlighted randomized phase 3 trials for patients with metastatic castration-sensitive prostate cancer

  • CAPItello-281 – Randomized phase 3 trial of Capivasertib + abiraterone vs. abiraterone for PTEN deficiency (NCT04493853)
  • CYCLONE 3 – Randomized phase 3 trial of Abemaciclib + abiraterone vs. abiraterone for high risk mCSPC (visceral met(s) or 4 or more bone mets by bone scan) (NCT05288166)
  • PSMAddition – Randomized phase 3 trial of 177Lu-PSMA-617 + standard of care vs. standard of care alone for metastatic castration-sensitive prostate cancer (NCT04720157)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References

  1. Fizazi K, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017; 377:352-60.
  2. James ND, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 2017; 377:338-51.
  3. Armstrong AJ, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2022; 40:1616-22.
  4. Davis ID, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019; 381:121-31.
  5. Chi KN, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2019; 381:13-24.
  6. Sweeney C, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015; 373:737-46.
  7. Fizazi K, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 2022; 399:1695-1707.
  8. Smith MR, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med 2022; 386:1132-42.
  9. Parker CC, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 2018; 392:2353-66.
  10. Yu EY. Another Advance in Metastatic Hormone-Sensitive Prostate Cancer May Change Standard of Care Options but Not Attitude Toward Clinical Trials. Urotoday Clinical Trials Portal. On-line: July 14, 2017.
  11. Yu EY. Enzalutamide and Apalutamide Now Offer Survival Benefit for Patients with Metastatic Castration-Sensitive Prostate Cancer, But How Do Things Change Now and What Should We Be Doing Next?. Urotoday Clinical Trials Portal. On-line: June 12, 2019.
  12. Yu EY. Metastatic Castration-Sensitive Prostate Cancer, The Advances Keep Coming With Chemohormonal Therapy. Urotoday Clinical Trials Portal. On-line: November 30, 2021.
  13. Jamaspishvili T, Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol 2018; 15:222-34.
  14. Musgrove EA et al. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 2011; 45:558-72.
  15. Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev 2016; 45:129-38.
  16. Choudhury AD, Beltran H. Retinoblastoma Loss in Cancer: Casting a Wider Net. Clin Cancer Res 2019; 25:4199-201.
  17. Sartor O, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2021; 385:1091-103.
  18. Sartor O, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. Ann Oncol 34, suppl 2, S1324-S1325; LBA13.