An Overview of Sequencing in mCRPC

Pedro C. Barata, MD, MSc:Treatment for metastatic prostate cancer has changed in the last few years. When we have a patient with metastatic prostate cancer, 1 of the first questions we need to answer is whether this disease is going to be sensitive to androgen-deprivation therapy [ADT] or not. For metastatic hormone-sensitive prostate cancer, we now have data from several large phase III trials showing that the combination of androgen-deprivation therapy plus androgen receptor targeted therapies—such as abiraterone or even enzalutamide or chemotherapy or docetaxel—improves clinical outcomes compared with androgen deprivation alone. When we have a patient with metastatic castration-resistant prostate cancer, assuming he progresses on ADT, we have 6 life-prolonging therapies available. Now that all changes because if we are using 1 of these 6 life-prolonging therapies early on in the context of the hormone-sensitive setting, then we are less likely to use it again in the castration-resistant setting. And so other options in the castration-resistant setting are dependent on what we chose for that particular patient in the hormone-sensitive space.

Treatment sequencing in metastatic prostate cancer remains a very, very important question, yet not completely answered. We do have a number of different systemic treatments that have the ability to improve clinical symptoms and improve overall survival. The question is, do we really know what the best sequence is for patients with metastatic prostate cancer? And what we know so far is, in general, we don’t. All the studies we’ve been conducting suggest that it might not be a 1-size-fits-all answer. And we might need to take into consideration patient characteristics, disease characteristics, and site of disease, etc, to help us define what the best sequence of therapies is for a specific patient.

When I think of all the sequencing of available treatments, I have to say that in my institution, the availability of clinical trials also impacts the treatments I’m going to choose. But in general, I would say that a good proportion of my patients will start on an oral androgen receptor targeted therapy, such as abiraterone or enzalutamide. And at time of progression, the clinical trials available in that setting, site of metastasis, clinical performance status, and patients’ beliefs do play a role, as well as genetics. They all play a role in what the next treatment I’m going to choose is for that particular patient.

In this particular patient, I fully agree with the way he has been treated so far. Perhaps if I were to treat him today, we now have data suggesting that he might have benefited from a combination of androgen deprivation therapy plus something else, which could be docetaxel or even abiraterone in the M1 hormone-sensitive space. However, back in the day, we didn’t know that, and so offering him androgen-deprivation therapy was the standard of care. Once he progressed, offering him enzalutamide was a very reasonable option. Other options would be reasonable as well. He was bone-only disease, not a lot of bone metastasis, so I would argue that abiraterone would be another reasonable option as well. I would probably have done the same thing, which would be to save radium 223 for when I would have more metastases, which happen to him at time of progression on enzalutamide.

And so I think that offering him radium-223 after enzalutamide was a very reasonable option because you allowed him to get all 6 cycles of radium, he kept his performance status at a good level, and he did not compromise future options for him. And we can see that he was offered chemotherapy 1 year later. And so I agree with the general approach to this patient.

Transcript edited for clarity.

Case: A 69-Year-Old Man With mCRPC Progressing on Therapy

July 2016

H&P:

• A 69-year old gentleman presented with nocturia
• PMH: unremarkable
• DRE, enlarged prostate
• PSA, 50.3 ng/mL
• TRUS and biopsy showed adenocarcinoma of the prostate gland; Gleason score 8 [4+4]
• CT scan showed minimal nodal involvement

Treatment:

• Started on ADT with initial PSA response - 15 ng/ml — August 2016

March 2017

8 months later, patient complained of fatigue and mild back discomfort

• Imaging with CT and bone scan showed two metastatic bone lesions (1 spine, 1 pelvis)
• PSA, 25 ng/mL
• Hb, 9.0 g/dL
• ANC, 1.7

Treatment:Enzalutamide

• Initial PSA response — 10 mg/ml but rising over one year later continued

March 2018

• PSA 30 ng/ml
• CT showed 4 bone metastases (2 spine, 2 pelvis) and diffuse liver lesions

April 2018

• Radium-223 initiated, patient received 6 injections

April 2019

One year later patient presented with increased lower back discomfort causing disruption in daily activity.

• CT showed new lymphadenopathy and diffuse liver lesions
• PSA 45 ng/mL
• Hb, 9.0 g/dL
• ANC, 1.6
• Treatment: Patient started on docetaxel, 6 cycles completed; achieved stable disease (Hb, 14.1 g/dL)