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Faster way for new drug approval in advanced prostate cancer


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Jim Marshall (not a doctor) said ...


The problem

Prostate cancer patients last much longer than most other cancer patients.


This bonus has a darker side. Men with prostate cancer have had to wait years longer to see the results of treatments tests (called clinical trials).


To take a local example, researchers led by Damien Bolton followed Victorian men who had had a radical prostatectomy between 1995 and 2000, and followed them up for about 10 years. Their report was published in 2014 (PMID: 23824175). Nineteen years! Some of the men studied can be expected to last more than 20 years - a total of twenty-nine years to see that result is anyone continues the study.


The problem has been that men and their doctors have been interested in survival - will men live longer on a treatment. And to see how many men survive and how many die, you have to wait a long time.


First solution

The first solution to the problem was to try the drugs first on men who had tried everything else first. On average they should die soon-ish and you get results in only a few years.


New solution - look at scans

Rathkopf and others did some research to help speed up the process. They looked at the data from a trial that had gone the full length - the PREVAIL trial. This trial had started accepting men in 2010, and published its results in 2016. 


Then, for each man in the study, they looked at:

  • how long it took for each man's scans to get worse; and
  • how long they survived.

There was a pretty good match - on average, if a man took a long time before the cancer seen on his scans got worse, he lasted a longer time.


So, this research has given us much shorter clinical study times. We don't have to wait to count heads in years to come. We just have to see if, on average, a new treatment keeps scans from getting worse longer than the best existing treatment.


Statistics - not a rule

It's important to note that this works on statistics - on the average of the men's times. As usual, the group giving the average will be well spread out. So, some men with shorter times to scan worsening will actually live longer than the average. And vice versa, some unlucky men with long times to scan worsening may not live as long. Results for all prostate cancer treatments are highly individual.


New trials are happening based on this new knowledge. Decisions will be made on how well the treatment affects what show up on the men's scans.


Using this new information

Two trials have looked at men whose primary hormone therapy is not holding the cancer, and their PSA is rising, but there is no sign of metastases (mets, new cancers growing away from the prostate). The PROSPER trial is looking at treating these men with Xtandi (Enzalutamide). The SPARTAN trial is looking at treating these men with Erleada (apalutamide). Both trials are looking mainly at how long a man takes to have his scans get worse.


This has already led to the FDA in the USA approving the use of Erleada (apalutamide) for men in this position, and similar approval is expected for Xtandi (Enzalutamide).


Newish guidelines for the Pharmaceutical Benefits Advisory Committee (PBAC) should make approval in Australia happen in a reasonable time.

... end Jim


JAMA Oncol. 2018 May 1;4(5):694-701. doi: 10.1001/jamaoncol.2017.5808.

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.



Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients.


To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS.


PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016.


Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment.


Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula.


In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ.


Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients.


clinicaltrials.gov Identifier: NCT01212991.

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