PSA Nadir 6 Months After Primary RT Correlates With Prostate Cancer Outcomes — Or does it?, MedPage Today May 22, 2024

[cujoe]

This article from MedPage Today is reproduced in full along with the link to the full access editorial comment is also provided. However, it has numerous hyperlinks to the the research cited within. The link to the MedPage article provides those links.

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PSA Nadir 6 Months After Primary RT Correlates With Prostate Cancer Outcomes — Or does it? Editorial questions prognostic, predictive value in contemporary practice,by Charles Bankhead , Senior Editor, MedPage Today May 22, 2024

Key Takeaways

PSA nadir 6 months after RT correlated with prostate cancer outcomes at 12 months and 5 years

Nadir ≥0.1 ng/mL associated with worse outcomes with RT ± ADT

Editorial questions relevance of findings in contemporary oncology practice

The nadir prostate-specific antigen (PSA) value 6 months after definitive radiotherapy (RT) had a significant association with long-term outcomes in localized prostate cancer, an analysis of almost 10,000 patients showed.

A 6-month PSA value ≥0.1 ng/mL as much as doubled the hazard ratio for metastasis-free survival (MFS) at 12 months. The hazard for prostate cancer-specific mortality (PCSM) and for overall survival (OS) increased by as much as 70-80% as compared with patients who had lower PSA values. Hazards remained elevated whether patients received RT alone or with androgen deprivation therapy (ADT).

Outcomes at 5 years also favored patients who had a 6-month PSA nadir <0.1 ng/mL, reported Christopher J. Sweeney, MBBS, of the University of Adelaide in Australia, and co-authors in the Journal of Clinical Oncologyopens in a new tab or window.

"The ability to have an early marker of treatment activity is appealing in localized [prostate cancer], where the natural history of the disease means it may take several years to demonstrate a benefit in PCSM or OS," the authors wrote of their findings. "Biochemical recurrence in men undergoing RT is the earliest clinically used marker of efficacy but has been only weakly correlated with PCSM or OS at the patient or trial level."

"Our data have immediate clinical relevance since a PSA at 6 months after RT is measured in routine clinical practice and could provide an early readout of treatment efficacy, particularly where novel systemic agents are tested along with ADT and RT in high-risk disease," they added.

Closer inspection of the data showed that a PSA nadir <0.1 ng/mL at 6 months post-RT "offers no or minimal prognostic value" after RT alone or with short-term ADT (stADT), noted the author of an accompanying editorialopens in a new tab or window.

"Most of the prognostic information can be captured from the baseline characteristics, and patients not achieving a very low PSA nadir still generally appeared to manifest favorable long-term outcomes," wrote Daniel E. Spratt, MD, of UH Seidman Cancer Center and Case Western Reserve University in Cleveland. "The prognostic value of PSA nadir post-RT appears primarily confined to the RT plus ltADT [long-term ADT] subgroup, although nearly 90% of patients with high-risk prostate cancer treated with lower-dose RT plus ltADT, even with a nadir PSA >0.1 ng/mL, did not die of prostate cancer 10 years post-treatment."

However, he continued, the predictive value of the PSA nadir warrants further consideration. Patients who have a suboptimal PSA response might benefit from intensified treatment with androgen receptor pathway inhibitors (ARPIs). However, most high-risk patients do not appear to benefit from such intensification as a result of favorable contemporary outcomes with RT plus ltADT.

"Consequently, early PSA response to ADT, irrespective of RT timing, could potentially guide more personalized treatment intensification strategies, which carry physical and financial toxicities," Spratt observed. "This hypothesis, while compelling, necessitates formal validation through completed randomized trials, and one should not assume that this subgroup will preferentially benefit from ARPI treatment intensification and use of this as a presumed predictive biomarker."

The emergence of prostate-specific membrane antigen (PSMA) PET/CT imaging for staging high-risk disease has led to unprecedented PCSM of about 1% at 6 years. In contrast, the landmark STAMPEDE trial of abiraterone (Zytiga) plus ADT for high-risk prostate cancer had a 6-year PCSM of 15%.

"These clearly are very different patient populations," Spratt continued. "Thus, as we look to design future trials in high-risk prostate cancer in the era of PSMA PET/CT, we must leverage the prognostic tools we have available to de-escalate therapy for most men with high-risk prostate cancer ... PSA nadir may be one additional variable to consider."

Several studies have sought to extract prognostic information about high-risk prostate cancer from post-RT PSA values. The largest of the studies was a pooled analysis of 2,400 patients enrolled in four Radiation Therapy Oncology Group trials evaluating RT and stADT. The results showed that a PSA >0.1 ng/mL after neoadjuvant ADT and before RT was highly prognostic.

Sweeney and colleagues reported data from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) initiative, which comprises individual patient data from 25 randomized trials of local therapy for prostate cancer. Previous analyses of ICECaP data established MFS as a surrogate for OS and that event-free survival lacked sufficient power to serve as a surrogate for OS.

The current analysis included 9,660 patients treated with RT alone (n=2,376), RT plus stADT (n=5,658), or RT plus ltADT (n=1,626). Each patient's lowest PSA value within 6 months after completing RT was recorded and categorized as <0.1 or ≥0.1 ng/mL. The primary outcomes were 12-month MFS, PCSM, and OS.

The data showed that 98% of patients treated with RT alone had a PSA nadir ≥0.1 ng/mL at 6 months, as did 84% of those who received RT plus stADT, and 77% of patients who received RT plus ltADT. A 6-month PSA nadir ≥0.1 ng/mL increased the hazard ratios for all three 12-month outcomes following RT with or without ADT:

RT alone: MFS (HR 2.24); PCSM (subdistribution HR 1.82); OS (HR 1.72)

RT plus stADT: MFS (HR 1.27); PCSM (subdistribution HR 2.10); OS (HR 1.26)

RT plus ltADT: MFS (HR 1.58); PCSM (subdistribution HR 1.97); OS (HR 1.59)

MFS at 5 years remained superior in patients who had a 6-month PSA nadir <0.1 ng/mL: RT, 91% vs 79%; RT with or without stADT, 83% vs 76%; RT with or without ltADT, 87% vs 74%.

Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007

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MedPage article is here:

PSA Nadir 6 Months After Primary RT Correlates With Prostate Cancer Outcomes — Or does it? Editorial questions prognostic, predictive value in contemporary practice,by Charles Bankhead , Senior Editor, MedPage Today May 22, 2024

medpagetoday.com/hematology...

Here is link to the accompaning editorial (full access):

Prostate-Specific Antigen Nadir Postradiotherapy in Localized Prostate Cancer: Is It Prognostic or Predictive?, Editorial, by Daniel E. Spratt, MD, Journal of Clinical Oncology, May 14, 2024

ascopubs.org/doi/10.1200/JC...

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Stay S & W, Ciao - cujoe

[cujoe]

NOTE: For those who questioned the impact of the proposed "embargo" on "Physician-Focused Publications", it is good news that the New England Journal of Medicine said it has rescinded its policy that cut off such publications from advanced access; i.e.:

NEJM scrapped language on its Media Center homepage that specified access for media producing content "for the public" and for freelancers writing for "non-clinical audiences."

As the JAMA paper cited in the above MedPage article is behind a paywall, it is only by the creation of content "for the public" and "non-clinical audiences" by web services like MedPage that we get the current information with which to make the best decisions about our healthcare. A rare win for us little people in a world progressively being run by big special interests.

NEJM Rescinds Embargo Policy Barring Physician-Focused Publications — Change follows a campaign by the Association of Health Care Journalists, by Kristina Fiore , Director of Enterprise & Investigative Reporting, MedPage Today, May 21, 2024.

medpagetoday.com/special-re...

[NPfisherman]

K9 Terror,

I like this statement from the article:

"Consequently, early PSA response to ADT, irrespective of RT timing, could potentially guide more personalized treatment intensification strategies, which carry physical and financial toxicities," Spratt observed. "This hypothesis, while compelling, necessitates formal validation through completed randomized trials, and one should not assume that this subgroup will preferentially benefit from ARPI treatment intensification and use of this as a presumed predictive biomarker."

Not everyone needs continuous treatment... the clinical trials will give us an idea of who can take a less intense treatment plan... biomarkers.... it will change the approach to treatment as the science can id candidates for less intensity...

The Science is Coming !!!! and it gives us hope !!!

Don Pescado

[cujoe in reply to NPfisherman]

DP/DD/NP - As you know, I am living proof that continuous treatment vs short-term up-front intermittent treatment is unwarranted for some subset of patients. I have voiced my opinion in the past that based on my own experience following BCR#1 back in 2016-17, anyone with a good response after an initial 3-mo ADT treatment (lupron in my case) has little to lose and much to possibly gain by testing for durable long-term "undetectable" PSA response before continuing with additional injections. (Again, in my case, lupron mono.)

Depending on testing intervals, the most one risks is a very short period (months) to test for response durability - and if PSA rapidly rises, then treatment can promptly resume. If not, as in my case, the patient gets a long treatment vacation (monitored by regular testing) and likely preserves the effectiveness of ADT for use later (when it is, in fact, really needed.)

That patients are routinely put on long-term, continuous ADT until failure seems to me to be the crudest application of an otherwise useful treatment tool; i.e. use it when it is needed and most effective, and do not waste its effectiveness driving PCa to early CR status. Maybe within this notion is some validation for Adaptive Theory, but at a minimum it offers a way to think about extending the effectiveness of existing treatments, while also recognizing the large potential to improve patient QOL. It also embraces the notion that the "minimum effective dose" is different for each patient (Justfor_ is the Master at that) - and it commonly departs significantly from the "max tolerable dose" that usually becomes SOC.

Stay Safe & Well, Ciao - cujoe

[NPfisherman in reply to cujoe]

Terror Dog,

The problem is that some people can not recognize the concept that MHSPC patients vary, especially when that treatment bias of continuous ADT is based on outdated studies like the Maha Hussain study from 2014 and other outdated studies. Continuous for those with significant disease that does not get the patient to a very low/ near undetectable status is not the question.

The question is how do we determine those that are good candidates, and until biomarkers are found, response to ADT /ADT plus ARPI seems to be the only guide that can be used. You were a responder from the get go, and so was I... Somatic and Germline testing offer other clues to responders. For those that believe exposure does not create resistance, an article to ponder:

ncbi.nlm.nih.gov/pmc/articl...

Salute to those like Justfor, yourself, and others that practice the concept that more is not always better. Some of our n=1 trials goes into data collected at centers of excellence. My MO stated that he and Dr Garcia at Cleveland Clinic are keeping track of those using SBRT in an oligometastatic state and doing IADT... I understand that Dr Denmeade is also collecting data on BAT patients.

QOL is the icing on the cake for those that do not have to be on continuous therapy. The monetary savings alone on drug pricing would be astronomical... cut demand and supply remains the same.... hmmmm...

Show me someone that endorses CADT for everyone, and I will show you someone that does not take these drugs or works with Big Pharma... In this day and age, targeted therapy will change cancer treatment forever, and end the randomness of treatment as we know it.... Nanoparticles, radioligands, antigen specific drugs, ways to improve immunotherapy, etc.. will drive the direction of treatment...

The Science will lead us to a more patient specific process with alternative/better treatment options than AR drugs...

Long Live the Science !!!

DP/NP/DD

[Justfor_]

Justfor_ knows, since high school, that intensity is the derivative of a quantity with time, denoted as dQ/dt. This foundamental differential equation seems too cumbersome to the medical community (two variables at the same time is way over the pay grade of the average clinician) that instead prefer to percieve intensity as the time pulse modulated train of a fixed quantity and preferably that of the maximum allowable quantity, thus reducing it to the simpler form of: Qmax/ΔΤ. It isn't any coincidence that Dr Bob Gatenby's first degree was in Physics.

[cujoe in reply to Justfor_]

Perfectly stated! And the reason why the mathematical minds are the ones that have taken up the role of understanding the theoretical nature of cancer genetics and metabolism. Ed Friedman, PhD, is another thoughtful mathematical theoretician that is providing insights into prostate cancer.

carenpharma.com/ed-friedman...