Is chemotherapy appropriate in this patient? What about local therapy?

This is a patient who&rsquo;s presenting at a relatively young age of 61 with a very high-risk situation. He&rsquo;s got symptomatic disease, lower urinary tract symptoms. He&rsquo;s got a large prostate with a high Gleason score. He&rsquo;s got multiple sites of bone metastasis. We&rsquo;ve known for a long time that hormonal therapy is going to be very effective in the beginning and sort of putting all of this into a remission, if we can use that term. But ultimately, patients do progress, and this is a person who&rsquo;s at very high risk, ultimately, for mortality from his prostate cancer. We have learned over the last couple of years from a couple of very pivotal studies that the early integration of chemotherapy is likely to prolong survival by quite a significant margin. Chemotherapy compared to no chemotherapy in a setting like this reduces the risk of death by about 40%, so that&rsquo;s quite a significant reduction in the long-term hazard of this. The survival benefits for a population treated with chemotherapy extend well beyond a year. So this is really an important consideration for this patient.

Charles Ryan, MD: The Role of Chemotherapy and Local Therapy

Would you consider bone-targeted therapy for this patient, and why?

Charles Ryan, MD: Bone-Targeted Therapy

What type of follow-up is needed for this patient during treatment and afterward?

This is a patient who I would probably see every three weeks while he&rsquo;s getting chemotherapy. I would give him 6 cycles of chemotherapy, so we would be seeing each other quite a bit right at the outset of treatment. Following the completion of chemotherapy, we would reassess the situation. I would hope that his PSA would be down, his performance status would be good. If there are soft tissue elements, I may consider repeating a CT scan after the completion of chemotherapy. I don&rsquo;t always repeat a bone scan because, in many cases, they can be quite confusing because of issues around bone scan flare and things like that. Once this patient has completed chemotherapy, provided that he is symptomatically well and his PSA is down and things look good, I might only see him every three months for a period of time.

One of the questions that comes up in a situation like this is local therapy. This is a person who presented to his physician at 61 years-old with a primary tumor that was very symptomatic. He was having lower urinary tract symptoms and even some hematuria. This is the type of patient who may benefit, in a palliative sense, from receiving local therapy, which might reduce his risk, for example, of pain or further hematuria. It might reduce his risk of further progression in the prostate which could lead to urinary retention or even kidney failure. For those situations, I think a discussion around local therapy is reasonable.

Charles Ryan, MD: Follow-Up Recommendations During and After Treatment

At the time of progression, would you go back to chemotherapy or use a secondary hormone?

Charles Ryan, MD: Comparison of Chemotherapy to a Secondary Hormone at the Time of Progression

Is abiraterone plus prednisone a concern considering the patient's history of diabetes?

Charles Ryan, MD: The Role of Abiraterone Plus Prednisone in Patients With Diabetes

Chemotherapy has been shown, based on the CHAARTED and STAMPEDE Trials, to be associated with a very significant survival benefit. In fact, the hazard ratios suggested at least a 30% to 40% improvement in overall survival with the addition of docetaxel chemotherapy within the first 4 months of starting androgen deprivation therapy in newly-diagnosed metastatic, hormone-sensitive prostate cancer.

This is a paradigm shift in this disease. We used to only use ADT in these patients, and, of course, patients would typically progress after a year or two on average. Now we&rsquo;re seeing with these two trials that in fact their survival can be extended by as much as 14 to 20 months, which is really profoundly longer. This has changed the way we treat hormone-sensitive metastatic prostate cancer in my practice, and I think it&rsquo;s really changed the international standard of care. In other words, patients who present, like this case, with newly-diagnosed metastatic prostate cancer should not just receive androgen deprivation therapy (ADT), but they should be offered docetaxel chemotherapy. Six cycles of docetaxel are typically given without prednisone, which is different from the way this drug is used in CRPC, and of course you have to discuss the pros and cons with this patient who&rsquo;s a very appropriate candidate for that approach.

One of the considerations with a patient with metastatic disease is, should you consider local therapy? Local therapy of course means surgery or radiation therapy. In fact, we have historically not done such a thing because most of the patients in the past were considered to have metastatic disease, and what&rsquo;s the point of taking out the prostate or radiating the prostate?

I think our thinking on this is evolving. There&rsquo;s increasing amounts of evidence, although no randomized data, that suggest that treating the primary site is associated with additional benefit. Historically, we would normally do radiation, for example, if the patient had bleeding or excessive pain or obstruction, for example, urinary obstruction. But in truth, the last few years we&rsquo;ve been thinking maybe we need to take care of the primary site. Maybe the primary site is a source for continued metastasis, and by radiating, or even, in some very functional patients, removing the prostate, we might improve survival.

William Oh, MD: The Role of Chemotherapy and Local Therapy

This patient presented with metastatic prostate cancer to the bone. Traditionally we would add bone-targeted treatments in this type of setting. By bone-targeted treatments I mean bisphosphonates or RANK ligand inhibitor, drugs such as zoledronic acid, or denosumab. In hormone-sensitive prostate cancer patients, the evidence of benefit has never really been clearer, and, in fact, two large studies have not suggested that there&rsquo;s a significant benefit to starting these treatments in the hormone-sensitive state. However, I do evaluate these patients in various ways.

William Oh, MD: Bone-Targeted Therapy

Historically patients with metastatic prostate cancer would be followed after starting a treatment like leuprolide acetate every three months. As long as they were responding and their PSAs would go down, they may see the urologist or the oncologist while they get their injections, and that type of intensity was really because there was nothing else you could do except the androgen deprivation therapy.

In the setting of docetaxel for hormone-sensitive metastatic prostate cancer, we&rsquo;re seeing these patients every three weeks obviously, because we&rsquo;re giving them chemotherapy during that initial period in addition to androgen deprivation therapy. So we&rsquo;re seeing them much more intensively.

William Oh, MD: Follow-Up Recommendations During and After Treatment

We know that these patients will eventually progress. If we assume that this patient may progress about two years after he completes treatment, that would not be an unusual timeline. And the question is, what should we do at that time? Should we start back on chemotherapy? Should we consider an AR-targeted therapy or something else? And this is a question that we really don&rsquo;t fully know the right answer to, partly because the CHAARTED and STAMPEDE patients have not been followed long enough to know whether there&rsquo;s an optimal sequence of next treatment.

I normally start metastatic CRPC patients who progress first-line with an androgen receptor (AR)targeted therapy. In this type of patient I might use abiraterone/prednisone, or enzalutamide. Some of these patients I&rsquo;ll also, if they&rsquo;re relatively asymptomatic, use a treatment like sipuleucel-T.

William Oh, MD: Comparison of Chemotherapy to a Secondary Hormone at the Time of Progression

Is abiraterone and prednisone a concern considering the patient's history of diabetes?

Metastatic Prostate Cancer with Charles Ryan, MD and William K. Oh, MD: Case 2