What Is the Evidence of Systemic Therapies (Alone or in Combination With MDT) in Oligometastatic mHSPC? APCCC 2022 Presentation - Mary Ellen Taplin
September 21, 2022
Mary Ellen Taplin, MD, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Joe O'Sullivan: Thank you Daniel. And it's a great pleasure now to introduce Mary Ellen Taplin, who will discuss the evidence for systemic therapies alone or in combination with MDT in oligometastatic, mHSPC.
Mary Ellen Taplin: Thank you. Here are my disclosures.
So the definition of the oligometastatic state has varied and much like the old adage about pornography. There has been the sentiment that I don't know how to define it, but I'll know what it is when I see it. We talked about promiscuous receptors, so I thought I would throw that in at the 2019 APCCC we voted on a definition, and 79% shows oligometastatic as being disease, amendable to ablative therapy, inclusive of radiation and surgery. With 33% inclusive of liver metastasis and 46% excluding liver metastasis. Anecdotally, I voted to include the liver mets as I have several patients in my practice with liver mets who have had ablative therapy and have had an incredibly indolent course.
So shown here are the CHAARTED and LATITUDE definition of low risk and low volume, which were both three or fewer bone metastasis. When I was assigned this talk, I started to think like, well, isn't oligometastatic prostate cancer, really just low risk or low volume and metastatic HSPC? So 35% in CHAARTED met this definition in only 20% in LATITUDE. Thus, LATITUDE was not powered to make any conclusions in the low volume or oligometastatic state.
The possible treatment options for oligometastatic HSPC are listed here, and include ADT alone, which until recently was a standard approach. Now, given data from a series of phase three trials, testosterone suppression, plus a novel hormone therapy, has become the primary mode of therapy, at least systemic therapy in most patients, if the immediate goal is possibly prolonging survival. Another option, is ablative therapy alone. And this most often chosen when the immediate goal is to delay the initiation of androgen deprivation therapy, or if the patient is not fit for androgen deprivation, or has a limited life expectancy. The other options are various combinations of these such as testosterone suppression, and metastasis directed therapy, but without a next generation hormone, and the combination of all available therapy, testosterone suppression, next generation hormone, and metastasis directed therapy to all known sites of disease.
Not covered in this presentation, but complicating decision making is whether metastasis is directed by conventional imaging or PET imaging. And I believe we've covered that pretty adequately in previous days. To fully understand the disease state of low volume metastatic prostate cancer, let's look at the data from the Canadian trial, which opened in 1999 and eventually was joined by SWOG, RTOG, and others, and reported 13 years later in 2012. The trial evaluated intermittent versus continuous androgen deprivation. The patients had prior radiation, even in the primary salvage setting and a PSA of at least three, one quarter of patients had a PSA greater than 15. The primary endpoint was overall survival and the median follow up was seven years up to 11 years. The median overall survival was eight years, and notably 60% of the deaths were not prostate cancer related. The overall survival is the same, as we now know from metachronous low volume disease detected by conventional imaging. And this may be the approximate overall survival that would be expected with PET detected disease treated with ADT alone, primarily because of the large burden of death from other causes.
The final point I want to make is that the long time required to reach the overall survival endpoint in this population, also demonstrated by the recent NHT trials in low volume metastatic prostate cancer. This is a point that Dan also made that the overall survival endpoint is unlikely to be the endpoint in any trials of oligometastatic prostate cancer. So some important unanswered questions in oligometastatic hormone-sensitive prostate cancer include: Can a proportion of patients be cured? What are the optimal treatments? And for which subsets of patients can systemic therapy delayed without compromising survival? When systemic therapy is given, what is the optimal duration? Is there an upper limit of metastasis for metastasis directed therapy, either alone or in combination with systemic therapies? Unfortunately, you don't have the answers to most of these questions.
The current data for NHT improving overall survival is a STAMPEDE post-hoc subgroup analysis in 900 patients, which was 47% of the original STAMPEDE abiraterone cohort. There was an overall survival benefit, hazard ratio was 0.66 in both high and low volume patients. Dr. Sweeney will present data on overall survival at ASCO from the Enzamet trial. Thus, the data on overall survival benefit is limited at this time, as would be expected with a long follow up needed to assess overall survival in this population. Overall survival is not going to be the primary endpoint of trials focused on this disease state. NHT with abiraterone enzalutamide apalutamide improves RPFS in low volume hormone-sensitive prostate cancer. RPFS thus is an achievable endpoint. An important question is if RPFS is the endpoint, should an NHT be included as in the control arm of any large trial in oligometastatic prostate cancer?
In order to get a sense of the current states of trials, oligometastatic prostate cancer, Dr. Ost our panel member here and his team in 2018 searched five large trial databases and identified 41 trials, in oligometastatic prostate cancer, only four trials were phase three. Oligo mets were PET detected in 60%. The trial landscape has changed a bit in the last three years, but this analysis gives a sense of the pipeline of trials, in oligometastatic prostate cancer. There are few phase three trials that will read out over the next five years as we'll be demonstrated on the following slides, the primary endpoints in the trials are varied. Turn your attention to the lower part of this table. You can see the systemic therapies being evaluated. In trials of synchronous or metachronous hormone sensitive, prostate cancer only 50% include a systemic therapy. Of those with systemic therapy, 29% are standard androgen deprivation. The other systemic therapies are chemotherapy, immunotherapy, NHT, and radium. As noted, most of these are phase one and phase three trials with the impact on the field, less certain. Next, I will display a few schemas of trials that I believe could be potentially practice changing.
The PLATON study is a Canadian cancer trials group study with eligibility of fewer than five metastasis, less than three of non-bone, synchronous or metachronous with randomization to standard systemic therapy, plus ablative therapy to the prostate, versus standard systemic therapy plus local ablative therapy to all sites of disease. The primary endpoint is failure free survival, and some secondary endpoints include RPFS and the others are displayed. Standard systemic therapy is at the discretion of the investigator in one stratification factor is the use of chemotherapy or NHT versus none of those.
The PEACE V or STORM Trials of phase two trial that evaluates patients with oligometastatic prostate cancer that is recurrent in pelvic nodes only, with fewer than four nodes. Patients will be randomized to six months of ADT and ablative therapy to the prostate if present, or ADT times six months plus ablative therapy, plus whole pelvis radiation. The primary endpoint is metastasis free survival, and some secondary endpoints are similarly shown.
The Veterans Affair trial, VA STARPORT is for men with oligometastatic HSPC with one to five lesions on PET. They will be assigned to standard systemic therapy or standard systemic therapy, plus PET directed local therapy to all sites of disease. Surgery or radiation is allowed. The primary endpoint is CRPC free survival at four years.
Couple other trials are shown here, not included is the STAMPEDE trial that Dan nicely went over just now. So finally, treatment recommendations to use local ablative therapy to all disease with the least treatment burden, plus consider androgen deprivation two years with or without a next generation hormone therapy. At the end of this time, if the PSA is less than 0.2 and scans show no evidence that disease some consideration to stopping therapy should be given. Other considerations include, not to use NHT if metastasis are only on PET scan and not on conventional imaging. To use NHT if the metastasis are seen on conventional imaging consider the patient's overall baseline status. And if there's a high chance of having a non-prostate cancer problem to limit the therapy. And it's really unclear at this time with the upper limit of metastasis is for SBRT. So some next steps, we need to do phase three trials, we need data to understand the role of these treatments in the state better. And we certainly need to understand the biology better to understand which subgroups of these patients potentially curable, which have early relapse, and understanding the biology and putting together database work will be important. So thank you very much.