Back in December 2017, Pfizer started a trial to explore whether the PARP inhibitor talazoparib (Talzenna) could be used in combination with enzalutamide (Xtandi) to effectively treat men with what are known as MSI-H or dMMR subtypes of metastatic castration-resistant prostate cancer (mCRPC).
It has long been suggested that talazoparib may be the most active of the PARP inhibitorts to enter clinical trials to date. The proof will, of course, be in the quality of the “pudding”.
Apparently the initial results of this trial in the first 200 patients were so promising that Pfizer converted the trial into a randomized, double-blind, Phase III trial (the TALAPRO-2 trial) in which any patient with asymptomatic or mildly symptomatic mCRPC can be randomized to treatment with either
- A placebo + enzalutamide or
- Talazoparib + enzalutamide
All patients entering the trial must have castrate levels of testosterone at the time of randomization into the trial, and they can not have had any other form of systemic treatment after they became castrate resistant. In other words, they must have progressed after a bilateral orchiectomy or after treatment on standard forms of medical castration (e.g., with an LHRH agonist), but they can’t have had any other form of systemic treatment (e.g., with drugs like docetaxel or abiraterone acetate).
This Phase III pivotal trial is currently enrolling a total of 870+ patients at multiple centers across the US, and it is hoped that this combination therapy can improve on patient outcomes compared to treatment with enzalutamide alone in addition to standard ADT.
The primary current trial for the current, extended trial is radiographic progression-free survival (rPFS) in unselected patients and in patients harboring DDR deficiencies from the date of randomization to first objective evidence of radiographic progression by blinded independent review, or death (occurring within 168 days of treatment discontinuation), whichever occurs first.
The PARP inhibitor talazoparib was approved by the US Food and Drug Administration in October 2018 for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer, but to date it has not been approved for use in the treatment of prostate cancer — and nor have any of the other three PARP inhibitors currently approved for use in the treatment of cancers: olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula).
When enzalutamide was tested alone (compared to a placebo) in the treatment of men with chemotherapy-naive mCRPC (in the PREVAIL trial), it demonstrated a significant improvement in rPFS and a small but significant improvement in overall survival at (see the original article by Beer et al. in the New England Journal of Medicine).
For the combination of talazoparib + enzalutamide to “outperform” enzlautamide alone, we are probably going to have to see the combination show a further considerable improvement of rPFS at 18 months after initial randomization (and ideally a further extension of overall survival benefit as well).
The currently estimated date for completion of the primary phase of the study (to meet the rPFS endpoint) is September 2022. The trial will actually run through to November 2024 before we can expect to see the secondary endpoints, which will include any impact on overall survival.
It is worth noting that all of the other PARP inhibitors are also now in Phase III trials for the treatment of prostate cancer, and these trials include:
- Study of olaparib (Lynparza™) versus enzalutamide or abiraterone acetate in men with mCRPC (the PROfound study)
- A randomized, double-blind, placebo-controlled, multicenter Phase III study of olaparib + abiraterone relative to placebo + abiraterone as first-line therapy in men with mCRPC (the PROpel study)
- A Phase 3, randomized open-label study of pembrolizumab (MK-3475) + olaparib versus abiraterone acetate or enzalutamide in participants with mCRPC who are unselected for homologous recombination repair defects and have failed prior treatment with one next-generation hormonal agent (NHA) and chemotherapy (the KEYLYNK-010 trial)
- A Study of rucaparib versus physician’s choice of therapy in patients with mCRPC and homologous recombination gene deficiency (the TRITON3 trial)
- A Phase III randomized, placebo-controlled, double-blind study of niraparib in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone in subjects with metastatic prostate cancer (this study is unnamed and is not yet recruiting patients)
The careful reader will not that each if these trials is slightly different, and so (of course) comparing the results of each of these trials to each other in due course is likely to prove challenging.
Filed under: Uncategorized | Tagged: inhibitor, mCRPC, niraparib, olaparib, PARP, Phase III, rucaparib, talazoparib |
THE "NEW" PROSTATE CANCER INFOLINK 
Too bad they don’t have an arm with carboplatin + enzalutamide.
Readers should note that as of 12/18, talazoparib is FDA approved for certain breast cancers. Like olaparib and rucaparib, it can be obtained off-label; I do not believe niraparib is FDA approved for any cancer just yet.
From anecdotal experience, olaparib appears to be the easiest drug to access for prostate cancer through insurance, but both rucaparpib and talazoparib may be accessible.
Allen: That may be the next question.
Dear Rick:
Apparently you didn’t read the complete article, which includes the very precise statement that, “The PARP inhibitor talazoparib was approved by the US Food and Drug Administration in October 2018 for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer.”
Similarly, niraparib (Zejula) is specifically approved for, “the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.” In other words it is approved for the treatment of cancer and could (hypothetically) also be used off label.
Sure I read it … right there in B&W!! That’s why I said “Readers should note …” to point out that talazoparib is available off-label, since that was not mentioned.
Thanks for the FDA niraprib indication that means it too is available off-label.
Myself, Joel Nowak, and one other advocate were asked by Pfizer to review this trial before it was launched. At that time there was a flaw — namely it did not require men to be tested for AR V7 prior to admission. Had that been required, it may have identified failure attributable to enzalutamide. Since somewhere between 20 and 40% of men are AR V7 positive, this potentially contaminates any results — or at least exposes the results to a challenge over this issue. It does not appear that the Phase III trial requires AR V7 testing either.