I previously described my treatment plans for my oligometastatic (<4 sites, in my case 2 lymph nodes in pelvis and abdomen) With a two-stage approach:
I explain this in somewhat more detail in my post "Why I Choose an Unproven Treatment". Many have asked me to post an update on the treatments, so here goes.
Antes de Nada (before anything), I wish to express my deep gratitude and joy in meeting with other HU-APC families while I was in Australia. Especially to Marnie and husband Ron and their whole delightful family that took such amazing and generous care of me during the week I spent in Sydney
First, I had "spot" targeting of the two new nodes identified on PSMA scan. This was 5 treatments in 5 days with external beam radiation, SBRT.
See below for some very new information on the effectiveness of metastasis targeted therapy that just is coming out for ASCO2022.
Then four weeks later (this month) I went to Perth, Australia for an experimental form of Lu177-PSMA treatments with a monoclonal antibody radioligand called J591. This is not the same as the Pluvicto treatments which use Lu-PSMA-617. The intention is to attempt targeting of all unseen micro-metastases and circulation cancer cells. It is an unproven regimen, though a clinical trial is underway.
The last of the two treatment infusions was just this last Friday. It is still at work inside my body, as evidenced by how I set of radiation detectors in the San Francisco airport and was detained for an hour despite providing documentation. Note that the level of radiation is below and danger level to others, less than 10 micro-Sieverts per hour at one meter. Probably more radiation from flying at 30,000ft+ for 20 hours.
I will not have any indication of actual effectiveness until follow up PSAs and PSA trends in the coming months. For now the molecular targeting radiation is "still at work".
So this is an early report on the experience. It is a very long way to Perth from Oregon! San Francisco to Sydney was 14 hours. Then 5 more hours flying across the continent to Perth. (No direct flights from the West Coast to Perth.) Perth was lovely and genteel. Great long walks along the Swan River and the enormous King's Park and Botanical Gardens. Wonderful, if expensive, restaurants crowded with friendly raucous Aussies.
GenesisCare (Theranostics AU) is in a nice suburb in a brand new building adjacent to St John of God Hospital, with state of the art equipment and amenities. Dr. Nat Lenzo and staff to careful attentive care of me and made sure I was comfortable. The isotopes arrived right on time. And IV infusion was easy-peasy. 15 min to go in then a saline drip for two hours before they released me by Uber back to my very comfortable hotel. No quarantine required, just some sensible precautions regarding prolonged closeness.
Basically, I had just two side effects. mild to moderate fatigued started on the second day and lasted until the 11th day after infusions. I could still do my long daily walks but needed an afternoon nap and did not feel like doing intense exercise in the hotel gym before it cleared. The other SE was some diarrhea. Lu-J591 is cleared by the liver and into the intestines via the bile. Messy and inconvenient but not severe. This too resolved by day 11. So it is, in all, a very easy treatment to tolerate.
Bone marrow suppression is the major risk. For anemia that some require transfusions, for low platelets that can also require transfusions, and low WBC counts. I had blood tests done before the 2nd infusion and my levels were all fine. virtually identical to my pre-treatment tests. Nat said that if it was going to be severe he would have seen a drop by that time as an indication. So all good.
"Metastasis-directed therapy" (MDT: either SBRT or surgical excision) in oligometastatic PC often fails in the long run. Over 60% of patients, even if the treated sites are completely resolved, will have recurrence nearby or distant within two years. (So that is why we added on this second form of treatment.) Many call this playing "whack-a-mole" and doubt the utility of it.
A study that was published as an abstract for ASCO 2022 today, argues otherwise. That it is beneficial for many, even without a second systemic therapy. This is true overall. And there is especially benefit for those with high-risk mutations (ATM, BRCA1/2, Rb1, or TP53).
Before someone replies by saying, "Oh that just shows improved progression-free survival (rPFS or cPFS), but does not prove improved overall survival (OS)." I will refer them to another ASCO 2022 abstract today that shows that PFS is indeed a valid surrogate intermediate marker for Overall Survival! That link follows at the bottom of this post.
meetings.asco.org/abstracts...
Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic castration-sensitive prostate cancer: A pooled analysis of the STOMP and ORIOLE trials.
Background:
Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response.
Methods:
Patients with omCSPC (< 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. Secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53. Cox proportional hazards regressions were fit to calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status.
Results:
Median follow-up was 52.5 months. Median PFS was prolonged with MDT (11.9 months) compared to observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (84%) as compared to the observation group (41%). On NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS -- in those without a HiRi mutation median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS -- those without a high-risk mutation experienced median rPFS of 22.6 months compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment.
Conclusions:
Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to optimize patient selection. Clinical trial information: NCT02680587.
The second abstract mentioned follows: (As above, so below!)
meetings.asco.org/abstracts...
Assessing intermediate clinical endpoints (ICE) as potential surrogates for overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC).
Background:
We hypothesized that radiographic progression free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration.
Methods:
We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of rPFS and cPFS as potential ICEs. rPFS was defined as time from randomization to radiographic progression (defined per protocol) or death from any cause whichever occurred first; cPFS was defined as time from randomization to date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. OS was defined as time from randomization to death from any cause, if patients had not died they were censored at the date of last follow-up. We implemented a two-stage meta-analytic validation model where conditions of trial level and patient level surrogacy had to be met. We computed the surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS.
Results:
IPD from 8592 patients randomized from 1994-2012 from 13 trials were pooled for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 75.6 months. In addition, there were 6227 rPFS and 6314 cPFS events. The median OS, rPFS and cPFS were 49.4, 26.8 and 25.2 months, respectively. The STE was 0.82 for rPFS and 0.84 for cPFS.
Conclusions:
Both rPFS and cPFS appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary endpoint as a surrogate for OS in phase 3 mHSPC trials and would expedite trial conduct. Validation of these ICEs in trials with drugs having other mechanisms of action is planned. Clinical trial information: Several.
SBRT Treatment Follow Up
Be careful: Pluvicto controversy, dammit!
