Answer: This is a patient who underwent radical prostatectomy 10 years earlier for Gleason 5 prostate cancer. He was followed for 3 or 4 years, during which time his PSA was acceptable and he stopped follow-up. Now, 5 years later, he is experiencing pain and has a PSA of 15 ng/mL. The first thing to do is obtain a scan to determine if the scan matches his complaint. In this case, the CT scan confirms metastasis to the sacroiliac joint.

Let’s walk through different scenarios in order to illustrate the decision-making process. A key issue is what happened after the patient had his radical prostatectomy. If he has a PSA rise post–radical prostatectomy, then the first thing to consider is salvage radiation. This is only appropriate for patients with very low PSAs (<2.0 ng/mL) and no metastatic disease. In this patient, however, he has metastatic disease, so salvage radiation is not appropriate.

If he has not had androgen deprivation therapy, then the first thing we would want to do is consider androgen deprivation [Figure 1]. This would typically include an LHRH analog, such as leuprolide acetate, goserelin acetate, or triptorelin pamoate; we may decide to add an anti-androgen, such as bicalutamide. This approach generally works well, as the androgen deprivation relieves pain and results in disease control that may last up to 5 years.¹

Now, another scenario is that disease recurrence was detected during follow-up and he received salvage radiation therapy. However, salvage radiation therapy failed and the patient went on to have a slowly rising PSA that was treated with androgen deprivation. After an initial response that lasted 5 years, the patient progressed to a PSA of 15 ng/mL and the metastatic disease was noted. In this scenario, the patient received hormonal therapy. So now we have a patient with metastatic castration-resistant prostate cancer (CRPC). We would determine our next treatment option based on the extent of metastatic disease and symptoms.

If the patient is significantly symptomatic, then we would first consider external beam radiation to the painful area. If you radiate the lesion, excellent palliation is possible 80% to 90% of the time.^2,3 Another option for symptomatic patients who do not respond to radiation would, in fact, be chemotherapy—especially for those with castrate-resistant, multifocal metastatic disease.^4-8 Trial outcomes confirm the survival and palliative benefits of chemotherapy with docetaxel; docetaxel/prednisone remains the first-line chemotherapy of choice for patients with CRPC.¹

If the patient has asymptomatic or minimally symptomatic metastatic CRPC (ie, serum testosterone <50 ng/dL), then we can consider sipuleucel-T. Another consideration would be to add an anti-androgen, such as nilutamide in combination with sipuleucel-T.⁹

Another facet of this treatment paradigm is where to place newer hormonal agents like abiraterone acetate, which has recently completed phase 3 testing within the chemotherapy-naïve metastatic CRPC setting.¹⁰ In an interim analysis, abiraterone was associated with a statistically significant improvement in radiographic progression-free survival (rPFS) and a strong trend for increased overall survival (OS), with a hazard ratio of 0.75. Even though this study did not meet its prespecified OS endpoint, should the FDA approve this agent, we’d have a new opportunity to treat patients with an effective non-chemotherapeutic, non–sipuleucel-T strategy in this situation.

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Answer: So, let’s say this gentleman had his first biochemical failure right after prostatectomy, and his second biochemical failure, as mentioned, after prostate bed irradiation. Today, he has a rising PSA (5-month doubling time), no symptoms, and negative imaging. For this patient, we’d use intermittent hormonal therapy. An open-label, randomized trial has found that intermittent androgen suppression (IAS) is not only non-inferior to continuous androgen with respect to OS, it is also associated with a better quality of life [Figure 2].¹¹ Given the 5-month PSA doubling time, we could, once again, use one of the LHRH analogs—typically, I would use leuprolide acetate or triptorelin pamoate—or a LHRH agonist in combination with an anti-androgen, such as bicalutamide.¹

However, it is important to recognize that it has never been convincingly demonstrated that early androgen therapy in the absence of metastatic disease is associated with better outcomes than if we’d wait until metastatic disease is present. Furthermore, it is clear that some patients will never progress to metastatic disease, so treating these men with androgen deprivation therapy will simply add unnecessary side effects and expense. Patients with a PSA doubling time >15 months rarely require any additional therapy, as their risk of prostate cancer–related death is very low.¹²

If we use IAS, we could use an LHRH analogue (with or without an anti-androgen) for 6 to 8 months, stop therapy, and let the testosterone recover while following PSA levels quite closely. If the PSA rises to 5 or 10 ng/mL, we could re-initiate therapy. This approach would allow the patient to feel less fatigued, be a bit more energetic, and potentially feel less depressed and more interested in sexual activity. In addition to these quality-of-life benefits, the patient may also potentially have more muscle or bone strength, with no detriment to OS. Because this patient does not have metastatic CRPC, there is no indication for chemotherapy.¹

In a patient with a non-metastatic prostate cancer with a slow PSA doubling time (>15 months), who is most likely not going to die from prostate cancer, the real measure of success is going to be how the patient feels. How well is he functioning? If you have patients who are feeling better and who are functioning well, then adding adverse events via androgen deprivation is not warranted.

I think the paradigm for advanced metastatic CRPC will be focused on maintaining better quality of life; I think we're going to be giving more in the way of combination therapy as well. In prostate cancer therapy, we've evolved toward a sequential mentality, where we give drug A, then we give drug B, and then we give drug C. Looking to the future, I think we are going to be using combinations of agents in new ways that are yet to be tested.

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