Evaluation of a High-Risk Prostate Cancer Patient

Alicia Morgans, MD, MPH:The case I’m going to talk about today is of a 75-year-old man with high-risk localized prostate cancer. His cancer was diagnosed because he had an elevated PSA [prostate-specific antigen] on routine exam. His PSA was about 35 ng/mL at the time of diagnosis, and he had an abnormal DRE [digital rectal exam]. When he underwent a biopsy, he ended up having a Gleason grade group 5 cancer. Importantly, he underwent staging CT [computed tomography] and bone scans that demonstrated that he appeared to have localized disease. He underwent treatment with radiation and a prolonged course of androgen deprivation therapy for his high-risk disease.

His PSA that had been somewhere in the 30s at the time of initial diagnosis actually declined to be undetectable by about 6 months after he initiated therapy. However, as he continued his androgen deprivation therapy, his PSA ultimately started to rise. About a year and a half after he started treatment, his PSA was again detectable. At this point he had some back pain and hip pain, and he had a PSA that was almost 30 ng/mL. Unfortunately, he underwent staging CT scans and a bone scan at the time that demonstrated some lymph nodes that had started to become enlarged in his pelvis and retroperitoneal area, and he also had some bone lesions.

He ultimately was diagnosed with metastatic castrate-resistant prostate cancer [CRPC] at that time and was started on enzalutamide. He tolerated the enzalutamide relatively well but unfortunately had progression of disease with a rising PSA about 8 months after starting his enzalutamide. At that point he underwent staging CT scans and bone scan again and was found to have progressive adenopathy on his CT scans, as well as progression of bone disease on his bone scan. He was started on docetaxel chemotherapy of standard dosing and received 4 cycles. But during that time, he ultimately didn’t tolerate treatment very well, developing some pitting of his nails, some neuropathy, and some fatigue, and he stopped his treatment with docetaxel.

His team considered other options for therapy and ultimately started him on cabazitaxel chemotherapy at the 20 mg/m²dose with prednisone daily, and he was also given GCSF [granulocyte colony-stimulating factor], or Neulasta [pegfilgrastim], to support his bone marrow.

At this point, if we considered this gentleman’s prognosis, we recognize that he was diagnosed with an initial high-risk localized prostate cancer. While he was getting his initial therapy that we hoped would cure him of his disease, he had progression of disease. He developed metastatic castrate resistance while on initial androgen deprivation therapy, which is actually a quite poor prognostic sign. His second sign of poor prognosis was that, in terms of disease control, he lasted for only about 8 months on enzalutamide.

Enzalutamide in the first-line metastatic castrate-resistant setting can typically last, or we hope will last, at least 12 months and sometimes a little longer. For this patient, disease control was only maintained for 8 months. These are 2 signs that this patient unfortunately had somewhat of an aggressive disease, and we know it’s already metastatic, making his prognosis somewhat poor and making it very important for us to find a highly effective therapy that uses a different mechanism of action than an androgen receptor [AR]—directed therapy to really get the disease down and allow him to maintain quality of life and disease control.

It’s important to consider in metastatic prostate cancer that biomarkers are a critical aspect of our treatment decision making. Biomarkers can include things like DNA-repair defect markers, and this is important in any patient with metastatic disease. We would determine this with germline genetic testing, as well as somatic genomic testing of the tumor tissue. Both of these are really important in understanding whether there may be a targetable DNA-repair defect mutation. We would target these mutations with things like PARP inhibitors. And in the third-line metastatic CRPC setting, this might be a good opportunity to use this treatment.

When we think about other biomarkers, things like AR-V7 [androgen receptor variant 7], I wouldn’t necessarily use that marker in this patient because we already know that the patient has been exposed to enzalutamide and likely has a cancer that’s resistant to an androgen receptor—directed therapy. Having a test that showed that he did or did not have the expression of AR-V7 wouldn’t necessarily change my decision making around giving him another AR-directed therapy. I wouldn’t do it because I already know that he’s developed resistance and actually has developed it in relatively short order.

That’s not a test I would order, but certainly I would order genetic testing and genomic testing to make sure I understood if this patient had a DNA-repair defect that can be targeted. When this patient was tested for DNA-repair defects, he did not have anything in his germline or in his tumor tissue that was targetable with a PARP inhibitor.

Transcript edited for clarity.

Case: A 75-Year-Old Male with Metastatic Castrate-Resistant Prostate Cancer

Initial presentation

2015

• A 75-year-old man presented with intermittent right hip pain and decreased appetite
• PE: abnormal digital rectal exam, otherwise unremarkable

Clinical workup

• PSA 38 ng/mL, LDH 415 U/L
• Staging bone scan and abdominal/pelvic CT scan demonstrated localized disease
• Core needle biopsy with TRUS showed adenocarcinoma of the prostate
• Diagnosis: Stage T2N0M0 — intermediate risk adenocarcinoma of the prostate
• Gleason grade group 5
• ECOG PS 1

Treatment and Follow-Up

• EBRT + ADT was initiated; stable disease, completed 18 months of ADT
  • 6-months follow-up at undetectable PSA

2017

• He complained of increasing hip pain, new onset back pain and urinary frequency
• PSA 29.4 ng/mL              
• Bone scan showed evidence of two osteoblastic lesions in the right hip (0.8 cm and 1.1 cm)
• Abdominal/pelvic CT showed a 2.1 cm left pelvic mass; evidence of inguinal, iliac and axillary lymph node involvement
• He was re-staged to T2N1M1b - IVB
• Started treatment on enzalutamide 160 mg PO qDay

2018

• After 8 months on enzalutamide PSA 60.7 ng/mL
  • Abdominal/pelvic CT showed enlargement of left pelvic mass and progressive adenopathy
  • Bone scan revealed progression of disease
  • Patient was started on docetaxel 75 mg/m2 IV q3W + daily prednisone 5 mg POq12hr
  • After 4 cycles patients suffered from mild bilateral digital neuropathy, pitting of the nails, fatigue and stomatitis; due to toxicities docetaxel was discontinued
    • PSA 75.1 ng/mL, LDH 870 U/L
  • Cabazitaxel 20 mg/m²IV q3W + prednisone 10 mg PO qDay + pegfilgrastim was initiated