The Rationale for ARN-509 in Nonmetastatic CRPC

Julie Graff, MD:Apalutamide is another second-generation androgen receptor antagonist, similar to enzalutamide. It, too, corresponds to the risk of seizure. It, too, brings down the PSA. It, too, can shrink tumors. It has not yet been shown to improve survival compared to placebo.

Apalutamide has similar side effects to enzalutamide. It should not be used in patients with a history of seizure. It could possibly decrease cognitive function. It could possibly increase the risk of falls. And I haven’t mentioned it yet, but all of these agents can also cause decreased bone density.

There is nothing worse than uncontrolled prostate cancer. Every treatment that we use to fight it has side effects. But compared to uncontrolled prostate cancer, they’re relatively minimal. We compare the toxicities of the agents available to us, and drugs like apalutamide are easier for patients to take than chemotherapy, and have much less effect on the bone marrow, fatigue, and neuropathy. So, I believe that the side effects are worth the efficacy that these drugs have.

The SPARTAN study looks at men with nonmetastatic prostate cancer who have a PSA doubling time of under 10 months. It randomizes those men in a 2-to-1 fashion to apalutamide versus placebo and follows them forward in time for side effects and toxicities. They collect data on the PSA, but that’s not known to the patient or physician. They check imaging studies every 4 months, until the patient develops metastases. The primary endpoint of this trial is metastasis-free survival with secondary endpoints including time to next treatment and overall survival.

The clinical significance of the SPARTAN study can be very profound. We have quite a few patients in this realm of having nonmetastatic castration-resistant prostate cancer, and we don’t have many things to offer them. The clinical impact is that we can use it and delay the time to metastases. My patients and I are very concerned when they develop a tumor on a bone scan or a CAT scan. If we can possibly delay that, we could delay some untoward effects of the cancer and potentially prevent death or delay it. I think that will have a very profound impact on the clinic.

The approval of apalutamide will cause these androgen receptor antagonists to move forward in the treatment of prostate cancer. It could also move up chemotherapy in some of the other treatments for metastatic cancer. These androgen receptor antagonists, being used earlier, will also make it more difficult to give patients abiraterone because of the cross-resistance between these androgen receptor antagonists and abiraterone. I can see us potentially using more chemotherapy.

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