Daniel P. Petrylak, MD

Daniel P. Petrylak, MD, professor of medicine and urology at Yale School of Medicine and coleader of Cancer Signaling Networks at Yale Cancer Center, discusses the design and results of the TITAN trial (NCT02489318) of apalutamide (Erleada) in patients with metastatic castration-sensitive prostate cancer (mCSPC).

The phase 3 TITAN trial randomized 1052 patients with mCSPC to receive 240 mg of apalutamide orally once daily or matching placebo both with androgen deprivation therapy (ADT). Patients were eligible if they had at least 1 bone metastasis with prior treatment limited to 6 cycles of docetaxel for mCSPC and if the last dose was up to 2 months prior to randomization. Patients were stratified based on having a Gleason score of 7 or higher versus lower than 7, geographic location in the United States or European Union versus elsewhere, and whether or not patients had received prior docetaxel.

The primary end points were radiographic progression-free survival (rPFS) based on CT or MRI, and overall survival (OS), each for up to 54 months, Petrylak says. Secondary end points included time to pain progression and time to initiation of cytotoxic chemotherapy.

According to Petrylak, at the interim analysis at 22 months, OS was improved with apalutamide with a hazard ratio (HR) of 0.67, and rPFS also increased with a HR of 0.48. At 48 months, the rate of OS with apalutamide was 65% compared with 52% with placebo. There was crossover of 208 patients (39.5%) from the placebo group following the interim results.

 The TITAN trial randomized 1052 patients who are castration sensitive. They had to have at least 1 lesion on bone scan or a CT scan. And they were allowed to have prior docetaxel and they had to be on ADT for castration-sensitive disease and those who started [must have received it] for less than 6 months. And they're stratified based on Gleason score, geography, as well as [whether] they've had prior docetaxel, and [were] randomized in a 1:1 basis to apalutamide, at 240 mg or placebo. And as I mentioned before, this trial did hit its OS benchmark: 33% reduction in the risk of death as well as a 52% reduction in rPFS.

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Daniel P. Petrylak, MD, discusses the design and results of the TITAN trial of apalutamide in patients with metastatic castration-sensitive prostate cancer.

TITAN Trial Finds Survival Benefit for Apalutamide in mCSPC

Daniel P. Petrylak, MD, professor of medicine and urology and coleader of Cancer Signaling Networks at Yale Cancer Center, discusses the impact of the approval of apalutamide (Erleada) in the metastatic castration-sensitive prostate cancer (mCSPC) setting.

Apalutamide is an antiandrogen drug that was approved by the FDA for treatment of patients with mCSPC in September 2019, having previously been approved for metastatic castration-resistant prostate cancer in 2018.

The randomized phase 3 TITAN trial (NCT02489318) of apalutamide demonstrated that 240 mg daily of apalutamide plus androgen deprivation therapy reduced the risk of death in patients with mCSPC by 35% compared with a placebo. It also delayed second progression-free survival and castration resistance.

Compared with abiraterone (Zytiga) and enzalutamide (Xtandi), which are also approved for mCSPC, apalutamide may have less central nervous system (CNS) toxicity, and is less likely to cause fatigue, according to Petrylak. Apalutamide also does not require corticosteroids, while abiraterone is generally given with prednisone.

 Given the fact that the survival benefits all appear to be about the same, apalutamide will reduce the risk of death by 33% in patients with CSPC and also reduce the risk of radiographic progression by [52%]. And that's within the same order of magnitude of the other drugs. One of the things I like to look at is toxicity. Apalutamide may have less CNS toxicity than other agents. That gives us an advantage over other drugs, particularly that we know that drugs like enzalutamide and abiraterone can cause fatigue. Also, compared to abiraterone, you don't need to use steroids, and that can be a problem in some patients. So there are a number of advantages that could occur based upon the [adverse event] profiles of each of these drugs.

Daniel P. Petrylak, MD, discusses the impact of the approval of apalutamide in the metastatic castration-sensitive prostate cancer setting.

The Impact of Apalutamide Approval on the CSPC Landscape

Daniel P. Petrylak, MD, professor of medicine and urology and co-leader, Cancer Signaling Networks, Yale Cancer Center, discusses the efficacy results from the CARD trial, which evaluated the radiographic progression-free survival (rPFS) of cabazitaxel (Jevtana) combined with either abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC).

The results showed that the use of cabazitaxel achieved better rPFS than either second-generation antiandrogen. This suggests that patients still have resistance to second-generation hormonal agents but, currently, there is no algorithm for understanding which agent should be administered and when.

Daniel P. Petrylak, MD, discusses the efficacy results from the CARD trial, which evaluated the radiographic progression-free survival of cabazitaxel combined with either abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer.<br />
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Cabazitaxel Improves rPFS in Patients with mCRPC

Daniel P. Petrylak, MD, professor of medicine and urology at Yale Cancer Center, discusses the data from the phase II EV-201 trial investigating enfortumab vedotin as treatment of patients with locally advanced or metastatic urothelial cancer previously treated with platinum-based chemotherapy or a PD-1/PD-L1 checkpoint inhibitor.

Enfortumab vedotin has a unique mechanism of action, says Petrylak. It is an antibodydrug conjugate that targets Nectin-4, which is expressed in lower levels in normal tissue cells in bladder cancers. This agent is able to deliver chemotherapy directly to the cancer cells in this patient population. Petrylak says this targeted therapy could be considered a &ldquo;smart bomb&rdquo; based on this activity.

The drug is also well tolerated. In the case of patients developing neuropathy on treatment, holding or reducing enfortumab vedotin caused the neuropathy to go away.  In addition, if the patient had a pre-existing neuropathy, holding or reducing the drug also caused the toxicity to reduce. Petrylak notes similar effects in regard to diabetes or rash in this patient population.

Daniel P. Petrylak, MD, discusses the data from the phase II EV-201 trial investigating enfortumab vedotin as treatment of patients with locally advanced or metastatic urothelial cancer previously treated with platinum-based chemotherapy or a PD-1/PD-L1 checkpoint inhibitor.

Enfortumab Vedotin Appears Well-Tolerated and Active in Advanced Bladder Cancers

Daniel P. Petrylak, MD, a professor of Medicine and Urology and co-director of the Signal Transduction Research Program at Yale School of Medicine, discussed results from the phase III RANGE trial for the combination of ramucirumab (Cyramza) and docetaxel in patients with urothelial carcinoma.

These findings demonstrated a 25% reduction in the progression-free survival (PFS) rate in the group of patients receiving ramucirumab plus docetaxel, Petrylak says. The toxicities did not significantly increase with the addition of ramucirumab to the standard treatment of docetaxel.

Combination Ramucirumab and Docetaxel for Urothelial Carcinoma

Daniel P. Petrylak, MD,&nbsp;professor of Medicine and Urology, Yale Cancer Center, discusses studies evaluating second-line treatment options in bladder cancer.

Daniel P. Petrylak, MD | Authors

Articles

TITAN Trial Finds Survival Benefit for Apalutamide in mCSPC

The Impact of Apalutamide Approval on the CSPC Landscape

Cabazitaxel Improves rPFS in Patients with mCRPC

Enfortumab Vedotin Appears Well-Tolerated and Active in Advanced Bladder Cancers

Combination Ramucirumab and Docetaxel for Urothelial Carcinoma

Evaluating Second-Line Treatment Options in Bladder Cancer