Contemporary Management of Hormone Sensitive Prostate Cancer - Alicia Morgans

April 9, 2019

Alicia Morgans presents a lecture on the contemporary management strategies for hormone sensitive prostate cancer with a focus on systemic therapy including chemohormonal approaches and the use of abiraterone for metastatic hormone sensitive disease.  In the discussion, Alicia compares and contrasts both the CHAARTED and STAMPEDE data and provides an update on treatment today, including evidence based data for treating the primary tumor.  She concludes with emerging data on metastatic directed prostate cancer.


Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Northwestern University. I am going to be speaking today about the contemporary management strategies for hormone sensitive prostate cancer. An outline of the discussion today will focus initially on systemic therapy, talking both about chemo-hormonal approaches and abiraterone for metastatic hormone sensitive disease and then touching on treatment of the primary, which is new data that is really quite important in this setting and also leads to some ongoing controversy regarding treatment of the primary. Then we'll touch on metastasis directed therapy to round out different therapeutic approaches that are currently being investigated and used for metastatic hormone sensitive disease. 

To consider systemic therapy, it's been actually a number of years now since we've had the initial data from the CHAARTED study and then follow up data from the STAMPEDE study suggesting that for metastatic hormone sensitive prostate cancer, the use of six cycles of docetaxel chemotherapy in addition to ADT was superior in terms of overall survival as compared to ADT alone, which had been the previous standard of care. You can see the survival curve on the left, which is the CHAARTED study published by Sweeney and colleagues back in 2015 demonstrating a 40% reduction in mortality for the use of this chemo-hormonal approach as compared to ADT alone. That was mirrored actually about a year later, pretty equivalently with the STAMPEDE study, again, a metastatic hormone sensitive population which found a 10-month improvement in overall survival with the use of chemo-hormonal therapy. 

Importantly, the STAMPEDE population was a little bit different than the population enrolled and CHAARTED. This population included patients who had high risk localized disease with a rising PSA as well as men who had truly metastatic disease. That benefit that was seen in the STAMPEDE study, at least in subgroup analyses, appear to be primarily centered on those patients who had overt metastatic disease. The CHAARTED study led us to some interesting observations in subgroup analyses that we actually have not yet ironed out fully. Remember the STAMPEDE study generally showed an improvement, as I mentioned, predominantly in the metastatic patient population. In the CHAARTED overall survival analysis for the overall population there was an advantage, but when we looked at the CHAARTED study by high versus low volume disease, both initially and in this follow up presentation and paper of the CHAARTED data, we found that the benefit in terms of overall survival was actually centered on those patients who had high volume disease versus those patients who had low volume disease, not really seeming to benefit from chemo-hormonal therapy as compared to ADT alone. 

High volume disease was defined in the study as patients who had visceral metastases or four or more bone metastases with at least one outside of the axial skeleton. Really this population that was supposed to be a more aggressive cancer defined by metastatic sites, not by biology because we just don't have the molecular information to tell us what's driving this potentially more aggressive phenotype, but again, as I said, the benefit in high volume disease was persistent in a follow up analysis with a median follow up of 53.7 months, but really never came to fruition even as the data matured in the low volume patient population. 

Importantly, the STAMPEDE data has not yet been analyzed in terms of high or low volume disease or at least if it has been analyzed, it has not yet been presented. We eagerly await the STAMPEDE data being characterized as high versus low volume so we can get an understanding of whether this is true for all patients with metastatic hormone sensitive disease, that there's this high low volume sort of surrogacy of disease phenotype and aggressiveness or whether this is really just study specific. As I said, awaiting disease volume data from STAMPEDE and we hope that that will come in the next 12 months or so. 

Moving along to abiraterone acetate, which is the other treatment option for patients with metastatic hormone sensitive disease, this was studied and was presented actually nearly simultaneously, one after the other, both at ASCO and then also published simultaneously in the New England Journal, in the LATITUDE study as well as in the STAMPEDE study in the abiraterone arm. In the LATITUDE study, patients who had de novo metastatic disease that was hormone sensitive and was high risk by two of the three of the following, Gleason greater than or equal to eight, presence of at least three bone lesions, or the presence of a measurable visceral lesion, benefited from the addition of abiraterone acetate to ADT as compared to ADT alone. This was actually true in STAMPEDE as well, though this was the same metastatic hormone sensitive population that we discussed in the previous study. 

Here you can see the survival curves with the LATITUDE survival curve on the left and the STAMPEDE survival curve on the right, demonstrating similar hazard ratios about just under a 40% reduction in mortality, highly statistically significant P values, both in this high risk population and then in this overall population of patients with metastatic hormone sensitive disease.

Importantly, the STAMPEDE data was actually reevaluated by the high risk criteria defined in LATITUDE as well as those patients who were not high risk, otherwise known as probably low risk, to see if the benefit with abiraterone acetate as compared to ADT alone was actually only among patients who had the high-risk disease as defined in LATITUDE or actually if it benefited all comers. What we can see on the right is that those patients who had high-risk disease like that defined in LATITUDE did clearly benefit. You can see that the hazard ratio here is 0.54, and that's highly statistically significant, but we can see on the left this is the low-risk population that was enrolled in STAMPEDE. There was a survival advantage, a hazard ratio that demonstrates about a 34% reduction in mortality, highly statistically significant, so the benefit of abiraterone in addition to ADT actually spans both the high and low-risk disease groups who were included in STAMPEDE. 

Now as I understand the coverage, at least in the UK and some parts of Europe, is not necessarily for all patients with metastatic hormone sensitive disease for abiraterone and is really centered in some places only on those patients with de novo metastatic disease that's defined as high risk, but we expect that this analysis of the STAMPEDE data may ultimately affect that indication and coverage. 

When we think about chemo-hormonal therapy versus abiraterone in the metastatic hormone sensitive population, I think it's hard to necessarily know which one is better, quote unquote. One way we can think about this, if we're not kind of making decisions with our patients and just trying to use patient preferences to make the choice, or disease volume preferences by the clinician to make the choice, is to look at the STAMPEDE data that actually was gathered in a period of simultaneous recruitment of patients to the chemo-hormonal and abiraterone arms, which we're fortunate enough to have. Now, this was not a preplanned analysis. It's not formally powered to be a comparison, but between November 2011 and March of 2013 patients were being randomized to both of these arms, the chemo-hormonal arm, and the abiraterone arm. 

Ultimately 566 patients were randomized to these two treatment arms and the investigators were able to an analyze in a post hoc fashion the overall survival comparing these two arms and they compared for prostate cancer-specific survival. As you can see here, there's actually no significant difference in overall survival or prostate cancer-specific survival. This is the Kaplan-Meier curve for overall survival where you can see those patients randomized to the standard of care ADT plus docetaxel arm in orange and those patients randomized to standard of care ADT plus abiraterone in blue just overlapping completely over the period of the study that they were followed. You can see the hazard ratio there, not statistically significantly different. 

I should note that there was a prolonged progression-free survival for those patients receiving abiraterone, which is really reflective of us taking testosterone out of the equation. With continuous abiraterone, you're going to have continuous suppression of testosterone and so it makes sense that the PSA would actually start to rise later. Progression-free survival as driven by PSA would happen later with abiraterone than with docetaxel, where patients had six cycles of docetaxel and then just continued on ADT alone. 

Additional studies are going to be reporting and have reported on systemic therapies for patients with metastatic hormone sensitive disease. You can see at the top left the schematic for the ARCHES trial, which is patients with metastatic hormone sensitive disease who could have received docetaxel and were randomized to receive enzalutamide plus ADT versus placebo plus ADT. We know that the radiographic progression-free survival was actually prolonged among patients who received enzalutamide as was reported at GU ASCO this year. The analysis was also stratified by disease volume as well as prior docetaxel. About 18% of patients in both arms received docetaxel. 

The TITAN study, which is on the bottom right, was reported only by press release and so we don't actually have real data to look at, but metastatic hormone sensitive population who could have received prior docetaxel, these patients were randomized to apalutamide or placebo plus ADT for both arms. Again, they were followed for radiographic progression-free survival and overall survival. From what we understand from a press release, this was unblinded because the study did meet its radiographic PFS and OS endpoints. 

On the upper left, we have the ANZUP ENZAMET study, which is again metastatic hormone sensitive prostate cancer patients who are randomized to enzalutamide and ADT versus a nonsteroidal antiandrogen plus ADT and they're followed to progression. These patients also could have received docetaxel. We hope to see some data suggesting whether this may be beneficial and expect to see some data hopefully within the next six months or so. Then on the right, the ARASENS trial, which is metastatic hormone sensitive prostate cancer patients who are randomized to receive either docetaxel and darolutamide or docetaxel plus placebo and all patients receive ADT. This study has finished accrual but has not yet met any of its primary endpoints. We do expect them in a few years.

This is important because all patients in this trial actually received docetaxel, so 100% received docetaxel and then they're randomized to receive darolutamide or placebo. This will help us have a better understanding, I think, of the impact of the combined approach of chemo-hormonal therapy plus an androgen receptor-directed therapy. I think we're all eagerly awaiting some data to help us tease that apart. 

When I think about personalization of systemic therapy, who should get abiraterone, who should get docetaxel? These are always really complicated things that I'm sure all of us are thinking about in the clinic and part of what makes our job fun, but when I think about docetaxel these are usually going to be, in my clinic at least, high volume patients who are younger and more fit, fit enough certainly to get docetaxel chemotherapy. There's often an interest in the people who end up being treated in this way with having six cycles of chemotherapy and then really just continuing on ADT alone without a daily maintenance medication. Certainly, some have financial difficulty getting abiraterone or have personal preferences for this approach. 

For those patients getting abiraterone, this would be all patients in my clinic at least who have low volume disease, because I do not treat patients with low volume disease unless they have a real reason or a personal preference that they really are asking for chemotherapy. I don't give them chemo-hormonal therapy. This would also be potentially older or frail patients who have high volume disease, patients who certainly can afford to get their abiraterone, that can afford the copay if they're unsafe to receive chemotherapy, or again, if they have a personal preference for this approach. 

Moving onto treatment of the primary, this has been an area of excitement and controversy recently, we saw data at ESMO that was published, data on treatment of the primary tumor with radiation in the STAMPEDE arm. This was, as I said, just published in the metastatic hormone sensitive population. Men with newly diagnosed mHSPC were randomized one to one to receive ADT with or without docetaxel as was standard of care, versus ADT with or without docetaxel plus radiation. It was a little bit of a different radiation plan than we typically use in the United States with once a week fractions for 6 weeks or 20 fractions over 4 weeks, but again, a little bit different than in the US, and they didn't address the nodal bed. About 18% of patients in both arms received docetaxel and they followed these patients for survival. 

Here you can see the overall survival curve for the entire population. Again, this is all patients randomized with or without radiation and best systemic therapy. You can see there's no statistically significant difference between those patients receiving best systemic therapy and radiation versus no radiation to the primary, but when we look at this survival by disease volume, we can see that in those patients who had a high volume of metastatic disease, and this is as it was defined in CHAARTED, so again, visceral disease or four or more bone metastases with at least one outside of the axial skeleton, you can see that there's actually, again, no survival advantage radiating the primary for those patients with high volume metastatic disease. 

If we look at the low volume metastatic disease patient population however, there is a significant advantage in terms of survival to radiating the primary versus best systemic therapy alone. You can see here a 32% reduction in mortality. This is highly statistically significant. From my view, although this was a subgroup analysis, it was planned prior to the analysis of the data. Actually, because so many patients were enrolled, over 800 patients, this to me is a practice changing advance so that patients who have low volume metastatic disease, in my clinic at least, receive counseling to consider radiation to the primary tumor. For the high volume patient population, I do not do that.

Interestingly and importantly, this question is still being studied. I think it's really important because we do have a lot of questions. Only 18% of the patients in STAMPEDE actually received chemo-hormonal therapy. We know that if we're going to use more intensive systemic therapy, perhaps we may negate the benefit of radiation. It's possible, so important to study. The PEACE-1 trial is really an exciting trial that we believe is nearly reached accrual. Patients with newly diagnosed metastatic hormone sensitive disease are randomized to ADT plus docetaxel for all, plus or minus abiraterone, plus or minus radiation to the primary. We will understand much better whether there's an improvement in terms of combination of docetaxel and abiraterone in addition to ADT and whether that improvement is still there when we add radiation to the primary or not. Really fascinating study, not quite 1200 patients expected to enroll. We hope that this will read out well. 

I do have some concerns that it may be underpowered to identify that benefit that we appear to only find in those patients with low volume disease associated with radiation, but perhaps it will be powered to see that difference. Then, of course, we wonder what the effect of best systemic therapy is going to be. Really exciting data that we expect in a few years. 

This SWOG study, S1802 is also looking at this metastatic hormone sensitive population and giving patients best systemic therapy for six months. For those patients who do not progress, they are then randomized to treatment of the primary tumor either with radiation or surgery versus no treatment of the primary tumor. We do expect that we'll have some improved understanding here after this study has enrolled to understand what the effect of surgery will be and to really clarify our understanding of whether the benefit of radiation to the primary is truly only really obtained by those patients with low volume disease. This will be an interesting study as well.

Who should treat the primary? In my clinic, low volume metastatic disease patients are offered radiation because of the survival advantage seen in the subgroup analysis in STAMPEDE. Anyone who has symptoms from their local disease also can benefit potentially from radiation to the primary. Patients enrolled on a clinical trial may receive radiation or surgery to the primary and I think that we have questions to answer and so those are certainly patients who may receive local therapy. Who should not treat the primary? From my view, patients with high volume metastatic disease don't appear to benefit from radiation, at least. I'm not sure about surgery, but I worry that they may not benefit from surgery either. Time will tell when we see the data. Those with a limited life expectancy or who are exceptionally frail also should not receive treatment to the primary, and then those who have contraindications to radiation certainly.

Finally, wrapping up with metastasis directed therapy, we do have a number of studies, but in the interest of time I'm just going to focus on one, Phase 2, prospective Phase 2, that looked at metastasis directed therapy in the STOMP trial. In this trial directed by Piet Ost, 62 patients who had a biochemical recurrence and were found to have metastatic disease on intensive imaging had metastasis directed therapy to those sites. They had to have less than or equal to three metastatic sites. Now importantly, the outcome here is ADT free survival. None of these patients were on systemic ADT. This is not a survival curve, but for ADT free survival there was a trend towards a prolonged ADT free survival with those patients receiving metastasis directed therapy as compared to those patients receiving surveillance. You can see that here.

I would caution everyone that the P value was not statistically significant. Although these appear to separate, it was probably underpowered to reach statistical significance. Also, I'd caution everyone to remember that this is not a survival curve. This is essentially time before ADT is initiated, which can be important to some patients, but is different than survival. 

Who should get metastasis directed therapy? These are, in my view, only patients on a clinical trial or patients who have symptomatic metastases, certainly. Those patients who should not get a metastasis directed therapy would be everybody else because this is, as I said, really still something that is under investigation. 

In summary, combination systemic therapy is now standard of care, not ADT alone anymore, from my perspective, unless you have an exceptionally frail patient. Chemo-hormonal or abiraterone are options for everybody, you just need to really choose the right treatment for the right patient. That is often a really important conversation between the physician and the patient and really thinking through the volume of disease and risk factors. Chemohormonal therapy may be optimal for men with high volume disease who are fit. Abiraterone can be used for men with high or low-risk disease, high volume, or low volume disease, and is good for men who are frail. Radiation of the primary should be considered for low volume disease because there is a survival advantage on the subgroup analysis in STAMPEDE. Metastasis directed therapy remains investigational, but is intriguing in select patients and certainly something that warrants further investigation in clinical trials. Thank you so much for your attention and your time.