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Prostate Cancer Personalized Therapy

CE / CME

Expert Think Tank on Applying the Latest Data to Individualize Treatment in Prostate Cancer

Pharmacists: 1.00 contact hour (0.1 CEUs)

Nurses: 1.00 Nursing contact hour

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: August 16, 2023

Expiration: August 15, 2024

Tanya B. Dorff
Tanya B. Dorff, MD
Rana R. McKay
Rana R. McKay, MD
Alicia Morgans
Alicia Morgans, MD, MPH
Michael Schweizer
Michael Schweizer, MD
David VanderWeele
David VanderWeele, MD, PhD
CME/CE Information

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Biochemical Recurrence

Alicia K. Morgans, MD, MPH:
Although most patients who have localized prostate cancer are actually cured with definitive local therapy, whether surgery or radiation, a subset of those individuals develops biochemical recurrence, defined as a rising PSA after definitive treatment, but in a hormone-naive setting before the start of ADT. Biochemical recurrence is not generally associated with visible metastases seen on routine imaging.

EMBARK: Enzalutamide With or Without Leuprolide vs Placebo Plus Leuprolide in Biochemically Recurrent PC

Rana R. McKay, MD:
A landmark study presented at the 2023 American Urological Association Annual Meeting was the randomized phase III EMBARK trial comparing enzalutamide alone vs enzalutamide plus leuprolide vs placebo plus leuprolide in patients with high risk, biochemically recurrent prostate cancer.22 Eligible patients (N = 1068) had a rapid PSA doubling time (≤9 months) and a PSA ≥1 ng/mL after radical prostatectomy (with or without postoperative radiotherapy) or ≥2 ng/mL after radiotherapy. The primary endpoint was MFS in patients treated with enzalutamide plus leuprolide vs placebo plus leuprolide. Key secondary endpoints included MFS (enzalutamide monotherapy vs placebo plus leuprolide), time to PSA progression, time to antineoplastic therapy, and OS.

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Phase III EMBARK: Efficacy

Rana R. McKay, MD:
The study met its primary endpoint of superior MFS demonstrated for enzalutamide in combination with leuprolide vs leuprolide plus placebo (HR: 0.42; 95% CI: 0.30-0.61; P <.0001).22 This trial did not really embed PSMA PET imaging, but this was a strikingly positive study with significantly improved MFS with both combination and monotherapy enzalutamide in this high risk population compared with leuprolide alone. I do think that it is practice changing. 

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Phase III PRESTO: ADT vs ADT Plus Apalutamide With or Without Abiraterone and Prednisone

Tanya B. Dorff, MD:
The phase III PRESTO study examined ADT alone or in combination with apalutamide with or without abiraterone and prednisone, in patients with biochemically recurrent prostate cancer.23 Eligible patients (N = 504) had a rapid PSA doubling time (≤9 months) and a screening PSA >0.5 ng/mL after radical prostatectomy, and no metastases detected by conventional imaging (CT or MRI). The primary endpoint was PSA PFS, with secondary endpoints including time to testosterone recovery, time to castration resistance, MFS, OS, and safety.

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PRESTO: PSA PFS

Tanya B. Dorff, MD:
The median PSA PFS was significantly prolonged in the doublet arm (24.5 vs 21.0 months; HR: 0.59; 95% CI: 0.42-0.81) and triplet arm (27.6 vs 21.0 months; HR: 0.53; 95% CI: 0.38-0.74) compared with the ADT control arm.24 

Because of its relatively smaller size and choice of primary endpoint, PRESTO was not nearly as impactful as EMBARK. I think many of us were left waiting for a more concrete endpoint like MFS to report out before adopting this therapy. Therefore, without having a stronger endpoint and knowing that there was more toxicity, this approach has not been widely adopted. Further scrutiny of toxicity and quality-of-life data will be important to help healthcare professionals guide patients when deciding about intensity of therapy in this setting.

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AR Inhibitor Monotherapy

Tanya B. Dorff, MD:
The results of EMBARK also raise the very interesting question of AR antagonist monotherapy. I think a lot of prostate cancer patients really want this because the toxicity profile can be favorable compared with castration, although there is more gynecomastia and mastodynia, so that is one tradeoff. I think we need to hear a bit more from that enzalutamide monotherapy arm. 

Rana R. McKay, MD:
The quality-of-life data for enzalutamide monotherapy will be interesting when reported because when evaluating treatment-related adverse events, those in the enzalutamide monotherapy arm are on par with leuprolide treatment. With enzalutamide monotherapy, there was more fatigue, more falls, more cognitive issues, and more heart related issues (almost doubling of cardiovascular risk) compared with leuprolide alone. The other thing to keep in mind is that monotherapy in the EMBARK trial’s enzalutamide arm was open label, in contrast with the leuprolide arms, which included placebo. This difference can have an effect on patient reported outcome data. 

Regarding the increased cardiovascular risk associated with enzalutamide, it will be interesting to look at prostate cancer–specific mortality and survival in the context of EMBARK. When you look at the PSA data, the patients are not really progressing based on their PSA values. It will be important to understand what the actual cause of death is in the patients enrolled in EMBARK.

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ADT Therapy for Patients With Biochemical Recurrence

Tanya B. Dorff, MD:
Some clinicians still ask whether we should be treating biochemically recurrent disease with ADT at all given the relative paucity of data showing prolonged survival with any treatment compared with observation. In the phase III TROG 03.06 trial, patients with previously treated prostate cancer experiencing PSA relapse (n = 261) or incurable disease (n = 32) were randomized 1:1 to receive ADT therapy immediately or after a time delay. The results did suggest that immediate ADT upon biochemical recurrence was beneficial compared with waiting until the presence of metastatic disease.25 I think this question is still out there because most trials have not addressed ADT vs a no-treatment arm. Some healthcare professionals wait until they can see the disease and then try to incorporate metastasis directed radiation into the treatment plan. Another set of questions will be how to actually use ADT in this situation: how much, how intense, and for how long? 

Early Use of ARSI vs Later During the Course of Disease

Tanya B. Dorff, MD:
There is a discussion in the mHSPC setting about when we intensify upfront therapy, are we using up a treatment that we could have used later? However, the data clearly show that early vs late usage is tremendously beneficial. I think in biochemical recurrence that same question is going to be raised. 

Rana R. McKay, MD:
Absolutely. You do not seem to get the same level of efficacy that you would expect when putting a patient on ADT after they have been on an AR inhibitor for a long time. That may be because they have developed more AR related mechanisms of resistance, AR mutations, or other things related to mCRPC. Something to keep in mind is that enzalutamide therapy in the EMBARK trial was intermittent, not continuous. Patients receiving enzalutamide stopped therapy after 36 weeks if their PSA was <0.2 ng/mL, and restarted at the time of PSA progression.22 This was different from the PRESTO trial, which had a single on period where patients were treated for 52 weeks before entering the follow-up, being followed in the case of PSA events.23 How many of the patients in the control arms of these studies went on to get an AR agent later? Again, this is the question of early vs late usage, and I suspect many of those individuals may not have seen an AR targeting agent later, which could affect interpretation of the data.

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