Understanding the CARD and PROfound Trials

Alicia Morgans, MD, MPH:In the CARD trial, patients who had metastatic castrate-resistant prostate cancer [CRPC] and had progressed on 1 androgen receptor [AR]—targeted agent, and docetaxel chemotherapy were randomized to receive treatment with the other androgen receptor–directed therapy or cabazitaxel at its standard dose, 25 mg/m², plus Neulasta [pegfilgrastim].

Patients were followed for radiographic progression and overall survival in this trial. We found that patients actually had prolonged progression-free survival as well as overall survival in the CARD trial. Importantly, the CTCAE [Common Terminology Criteria for Adverse Events]—graded events, which talk to us about the toxicity of the agents, suggested that the chemotherapy did not have any adverse effects that are really outside its traditionally considered adverse-effect profile. There were actually more grade 5 adverse events leading to death in the patient arm of patients who were treated with the AR-targeted therapy. There were fewer grade 5 events in those patients who received chemotherapy.

Importantly, these patients had a better pain response when they were treated with chemotherapy, probably because of better disease control. We saw that this was really what I consider a practice-changing study in that it defined for us a path forward in the third-line setting in metastatic CRPC, where we had not actually had trials that who us what happens to patients who have already received first and second-line treatments for metastatic CRPC.

These patients seemed to tolerate the treatment actually quite well—as I said, both in terms of CTCAE and patient-reported outcomes—with their overall quality of life also being reported to be better when they were treated with cabazitaxel as compared with the androgen receptor—directed therapies at the 3-month assessment by the overall quality-of-life measure, the FACT-P [Functional Assessment of Cancer Therapy-Prostate]. The drug was actually quite well tolerated and ultimately improved survival in this heavily pretreated third-line metastatic castrate-resistant prostate cancer population.

When I think about using a second AR-targeted agent after exposure to and progression on a prior AR-targeted agent in the metastatic CRPC setting, I really talk to patients about the inadequacy of that therapy, that sequencing, and my expectation that the treatment is probably not going to help them. This has been demonstrated certainly in the control arm of the CARD trial, but it’s also been demonstrated in other settings. For example, in the PROfound phase III trial that looked at men with metastatic CRPC who had DNA-repair defects, men were randomized to treatment with olaparib or the other AR-targeted agent [enzalutamide or abiraterone]. This was in patients who had already progressed on chemotherapy and an initial AR-targeted agent. We saw that the radiographic progression-free survival of that control arm, the second AR-targeted agent, was about 3½ months, which is very similar to what we saw in the CARD trial, which was about 2½ months or so.

We consistently are seeing in patients who have already progressed on an initial AR-targeted agent—whether they progress within 12 months, as they did in the CARD trial, or whether they simply progress at any time point, which they did in the PROfound trial—that the expected time to controlling disease and preventing radiographic progression is really short. And the reason it’s probably around a 3-month time point is because that is when they were doing the radiographic assessment. Most of these patients are progressing on the first or the second radiographic assessment, really suggesting that we’re not controlling the disease growth.

There are patients, a few patients, who may respond to a second AR-targeted agent. Usually I think about use of enzalutamide after abiraterone being potentially a little more effective. But this is not my first choice, and it’s something I highly recommend patients consider not doing, because we do know that the mechanisms of resistance are quite similar. Especially in settings where we have an aggressive cancer and we need to control the disease, this is not expected to really do that and actually could waste time for patients leading to decline in functional status, potentially closing the door for them to get something like chemotherapy, which may actually prolong their life. But this has to be given in patients who are well enough to tolerate it.

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