Rationale for AR Targeted Therapy in CRPC

Daniel J. George, MD:Back to our case, this is a patient who presented with locally advanced, high-grade disease. Early on, he was put on androgen deprivation therapy and showed initial response but quickly, within a year, developed castration-resistant disease with a rapidly rising PSA [prostate specific antigen]. There are 2 points that are really critical about that. We mentioned 2 earlier: The short course and maybe incomplete PSA response to primary hormonal therapy really predicts a bad outcome in these patients. Secondly, it suggests that androgen deprivation upfront may have been incomplete.

Drugs like enzalutamide, abiraterone, and apalutamide offer the opportunity to be more complete in our androgen blockade. So they are not only blocking testicular testosterone, but testosterone activity produced either by the tumor or the tumor microenvironment, also blocking it either at the production level or at the receptor level. Those mechanisms have now been validated for improving survival and disease progression in patients with castration-resistant disease, and I think they’re really an important cornerstone in how we manage these patients.

We know that they’re incomplete, too. These patients are going to go on to secondary resistance, or more complete androgen receptor-refractory disease. In that setting, we need to start thinking about additional therapy. So back to our case, that’s the setting in which the patient developed osseous metastatic, symptomatic disease, alkaline phosphatase elevations, and other signs of complications related to bone metastases. That’s why, in this case, the patient was treated with radium-223. Radium-223 has shown a survival benefit in that exact setting, and it also specifically targets that bone microenvironment.

One of the real biomarkers associated with that is a decline in alkaline phosphatase. We see that in this case. The patient’s alkaline phosphatase drops from 268 to 80. That, in general, is associated with a good treatment outcome and longer survival.

When we’re treating a patient with drugs like enzalutamide or abiraterone, we commonly see an initial response by PSA. We may also see adverse effects that are associated with these drugs. Sometimes it’s difficult to tease out what’s an adverse effect from the drug and what’s really related to the disease. To me, PSA becomes a marker for reevaluating that symptom profile. If the patient’s PSA is rapidly dropping, other markers like alkaline phosphatase are responding, and there are indications of disease response, maybe objective disease is regressing on CT [computed tomography] scan. That gives me confidence that the drug is working. This is probably not a disease progression profile. Those symptoms that the patient may be experiencing could be directly or indirectly related to that treatment—enzalutamide, or abiraterone, or what have you.

As that patient goes on in their course, as that PSA reaches a nadir and begins to rise, particularly as the PSA rises, that’s my cue to start looking for symptoms and reevaluate. Are any of these things getting worse? The patient may not necessarily report this, but I’ll ask, “Are you moving around less?” “Are you doing less activity?” “Are you sleeping less?” “Are you having more pain?” “Are you changing any of the medicines that you use for pain?” “Are you having any issues with appetite or with energy?” These are the kinds of symptoms that I think can be subtle, and they’re not going to be cumulative from enzalutamide or abiraterone. They’re generally going to be stable from that. But, in the setting of a rising PSA, that’s where we see them. In both the PREVAIL study and COUGAR-AA-302 study, a median time to PSA progression was around 11 or 12 months. The median time to patient-reported outcome, the FACT-P [Functional Assessment of Cancer Therapy—Prostate] score dropping, was about the same—11 or 12 months. Even physician-reported performance status changes. The median time to performance status declined in the COUGAR-AA-302 study. It was, again, 11 months. All of these things tend to happen around the same time period. To me, that’s really a cue to say, “Are these symptoms?” “Do I think these symptoms are real?” “Do I think these symptoms are related to disease?” It may not be radiographic progression. That may come 6 to 8 months later, but that’s an indication to me that that bone metastatic disease is driving a symptom change. I’m going to use drugs like radium-223 to treat that sooner rather than later.

Transcript edited for clarity.

mCRPC Treated With Radium-223 Therapy

January 2015

H&P:

• A 71-year old gentleman presented with urinary incontinence
• Past medical history: HBP controlled with lisinopril
• On digital rectal examination prostate was enlarged
• Patient was asymptomatic

Imaging:

• Transrectal ultrasound and biopsy revealed adenocarcinoma of the prostate gland with a Gleason score 9 [4+5] with 9 of 12 cores positive
  • PSA, 10.2 ng/mL
• CT scan was negative for metastases
• He was started on a 3-month depot injection of leuprolide 22.5 mg and treated with 7800 cGy IMRT

April 2016

• Patient returned for 3-month injection; his PSA level increased to 47 ng/mL
  • CT/Bone scans were negative for metastases
• He was started on enzalutamide
  • PSA, 12 ng/mL

October 2016

• 6 months later the patient complained of severe fatigue and lower back pain
  • Imaging with CT and bone scan showed multiple metastases of the spine and pelvis
  • PSA levels increased to 76 ng/mL
  • ALP, 268 U/I
• Radium-223 therapy was initiated in addition to continuing enzalutamide
• After 3 infusions of radium-223
  • PSA declined to 31 ng/mL
  • ALP decreased to 80 U/l
  • CT scan showed no new bone metastases
  • Fatigue decreased, and patient’s physical activity increased