Impact of ARN-509 on Nonmetastatic CRPC Treatment


Charles Ryan, MD:ARN-509, now known as apalutamide, is the derivative of bicalutamide that has a much greater potency against the androgen receptor, and, in fact, was specifically designed to target the amplified androgen receptor. As the disease progresses, in about 75% of cases, the androgen receptor will amplify. And so, that’s the critical biological link, in a way.

The early phase I and phase II data with apalutamide suggest a very high rate of clinical response in terms of PSA reduction in the castration-resistant prostate cancer setting. Limited efficacy, but some efficacy, in patients who have abiraterone-resistant disease. But probably its greatest efficacy is demonstrated in patients with nonmetastatic castration-resistant prostate cancer, as well as those with metastatic castration-resistant prostate cancer who have not received prior therapy with either abiraterone or enzalutamide.

The SPARTAN trial is a randomized phase III placebo-controlled trial of apalutamide versus placebo in nonmetastatic castration-resistant prostate cancer. The reason that a placebo was used is that there is no standard of care in the nonmetastatic prostate cancer, and at least in the eyes of regulatory authorities, observation or surveillance is the standard of care in that group of patients. So, this is testing whether integrating apalutamide earlier in the clinical course will lead to an improvement in metastasis-free survival as the primary endpoint and overall survival as the secondary endpoint. The study is fully accrued. We expect data relatively recently demonstrating how and what extent apalutamide may affect metastasis-free survival in this group of patients.

The treatment of nonmetastatic castration-resistant prostate cancer really has 2 goals. One is to improve overall survival in the long run, but in doing so, it would be nice to preserve a metastasis-free state. The development of metastasis is really the development of a lethal phenotype of prostate cancer. It’s very disconcerting and troublesome for patients. It can lead to pain, it can lead to fractures, and it can lead to all kinds of comorbidity or morbid complications. And so, by preventing those from happening, or delaying that even, we can improve the clinical benefit for our patients. So, the goal of using metastasis-free survival is an intrinsically good goal, I think, in that we are preserving patients in a metastasis-free state.

My counseling with patients in this setting is the use of therapy centers around what I call the 3 Ps: preventing metastasis, preserving good function and good quality of life, and prolonging life. And if we’re able to achieve all 3 of those Ps, if you will, with 1 therapy, it will represent a significant new benefit on a significant new addition to the pharmacopeia for castration-resistant prostate cancer.

The approval of apalutamide will make available the treatment in a space where there was no treatment previously. There’s really no better way to put it than that. It will also bring into the clinic a second AR-targeted drug that may have improved safety profile over the prior one, enzalutamide. I think it’s important that we study that question. I don’t know that it will necessarily improve the sequencing of these drugs because I suspect that clinicians will want to choose either apalutamide or enzalutamide and won’t do one then the other. But that question actually remains to be explored, I think. And it’s the addition of a new concept in that it’s looking at an earlier intervention in castration-resistant disease, and it’s moving the therapies progressively earlier and earlier. I think that one of the general trends we see is that as we successfully move therapies earlier and earlier, we actually see greater benefit from those therapies compared to not giving them.

Transcript edited for clarity.

January 2014

  • A 66-year old retired African American male presents with reduced urinary flow and hematuria.
  • PMH: High blood pressure. Currently taking enalapril 10 mg.
  • FHx: Father lung cancer — age 74.
  • Patient walks 3 miles a day.
  • PSA 9.8 ng/ml
  • Prostate biopsy shows Gleason 7 (4+3) prostate cancer
  • Undergoes robotic-assisted laparoscopic prostatectomy (RALP) and pelvic lymph node dissection (PLND)
  • Results show:
    • pT3b (focal extracapsular extension and seminal vesicle invasion) — margins negative
    • N1
    • M0
  • Post-operative PSA=0.64 ng/ml
  • Patient undergoes adjuvant radiation therapy and is started on leuprolide acetate.
  • PSA drops to undetectable levels

January 2016

  • PSA starts to rise to 0.3 ng/ml
    • Repeated 3 months later — 0.7 ng/ml
    • Bone scan and prostate-specific membrane antigen (PSMA) scan both negative
    • Diagnosis nonmetastatic castration-resistant prostate cancer (CRPC)
    • Patient declines additional therapy at this time

November 2017

  • PSA continues to rise over the next 18 months going up to 9.8 ng/ml
  • Bone scan shows lesion in the left superior pubic ramus
  • Patient is asymptomatic
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