Coronary microvascular dysfunction: A review of recent progress and clinical implications
Liu's Insights On Navigating The Fragility Of Phase 3 Trials
Yufei Liu, MD, PhD, discussed the importance of careful data interpretation to accurately assess the efficacy of new treatment options in oncology.
The design and interpretation of phase 3 trials in oncology are pivotal for advancing therapeutic strategies. However, according to Yufei Liu, MD, PhD, there are several complexities of trial designs, particularly regarding crossover methodologies.
As crossover designs spark considerable debate within the field, Liu, assistant professor of radiation oncology at City of Hope, emphasized how patient transitions between treatment arms can significantly impact trial outcomes, potentially skewing results and affecting clinical decision-making.
"I think the fragility of a clinical trial allows us to assess clinical trials in a different way...If we see a fragile, statistically significant result, it suggests that we may want to design another trial—potentially a larger one with a bigger sample size—to ensure that what we're seeing is not just a statistical fluke," said Liu in an interview with Targeted OncologyTM.
In the interview, Liu highlighted the critical need for meticulous data interpretation to ensure that the efficacy of new treatments is accurately captured and understood.
Targeted Oncology: Could you elaborate on the potential biases introduced by crossover designs in phase 3 trials and how they impact the validity of results?
Liu: In terms of crossover designs, there are not a lot of clinical trials that utilize that approach. But for ones that do, it certainly introduces the problem of, how do you interpret that data when patients do cross over? In using the technique of the fragility of the phase 3 clinical trials that I assessed, we essentially are directly addressing that question by crossing patients over from one arm of a clinical trial to another arm, and using that approach, we can see that it can significantly affect the results of clinical trials, because sometimes it only takes 1 or 2 crossover patients, and oftentimes only in the single digit numbers, to see a dramatic difference in the significance of a trial.
I think we do have to be careful when doing these crossover designs. One way of assessing this is potentially looking at the outcomes of the patients who crossed over, taking note of that, and then looking at the results if they had not crossed over, and seeing if they still see the same conclusions as with the crossovers.
What are some of the challenges in selecting primary end points for phase 3 trials in oncology?
The gold standard of the end points is always going to be overall survival for the phase 3 trials. However, unfortunately, we are not always able to get enough sample size to get meaningful overall survival data, or sometimes overall survival takes a long time to see the difference. For certain types of cancers where survival is very good, we often use surrogate end points, because oftentimes we do want to publish the results of trials before overall survival data can become mature, which sometimes can take 10 years or more. We have to use surrogate end points such as progression-free survival. Sometimes we use local control or distant metastasis-free survival. There is certainly some danger to using these end points, because, in a way, the more end points that we use, the more chances that we can find an end point that just happens to be more statistically significant. Whereas overall survival is the golden end point, these other end points are a little bit harder to interpret because you can find that one end point is significant, but it does not affect the overall survival. In some respects, it leaves you wondering, is this really a meaningful end point, or how valuable is that? I think we do have to be careful in selecting these other end points, and I think this requires a conversation when designing the clinical trial with practitioners out in the field as to what is truly meaningful. Which outcomes do we think can truly stand in as surrogates for overall survival? I think that is an important conversation to have at the beginning of designing these trials.
How do you think surrogate end points impact the perceived fragility of trial outcomes through oncology?
If we are looking at something like progression-free survival, oftentimes it is a little bit easier to see differences in progression-free survival compared with overall survival. From that standpoint, the trials can seem a little bit less fragile if you do use the surrogate end points, just because it allows you to see a more significant result. However, when looking at that, it does not necessarily mean that the overall survival data itself is not fragile. Sometimes these surrogate end points can mask the fragility of trials. It is almost like you are choosing whichever end point gives you the most significant P value. In terms of your most important end point, which is their survival, it is sometimes that can be masked in these circumstances,
Can you discuss the role of subgroup analyses in phase 3 trials and how they contribute to or mitigate the fragility of these results?
Subgroup analyses are certainly a very tricky issue. I think one of the things is that whenever clinical trials are designed, we always want to make sure that we have enough patients so we have enough power for in the studies to detect a certain clinical end point up to a certain magnitude. Whenever we do subgroup analyses, these are essentially unplanned, so we certainly do not have enough power to detect differences.
However, sometimes we are able to find interesting differences. If we find that [in[ the overall group of patients that were assessing, some certain intervention was not significant, oftentimes we like to see, is it because of certain groups of patients, certain characteristics? In that respect, these trials can still be beneficial and give us information about that. However, I would caution that, because the trial is not powered to detect those differences, this is more of an exploratory end point. It is very hypothesis generating. Potentially, we want to design a future clinical trial addressing the question that we addressed in our subgroup analysis if we found something interesting. However, I would say these subgroups analyze themselves because they are not powered, and the trial was not designed to assess those. It is hard to make a conclusion from the overall trial itself, and I would say from the fragility standpoint, because it is not powered, it is hard. Oftentimes, the results tend to be very fragile as well. It does not take very many patients, oftentimes less than 3 to 4 patients or so flipping from one arm to another, to see that the results will disappear.
How do you suggest oncologists balance the results of phase 3 trials with real-world evidence?
Whenever we see the results of phase 3 trials, whether they end up being positive or negative, we also have to think about the clinical significance of what we are testing as well. Oftentimes, certain agents have been used for a long time. We have to try to incorporate all the data that has been found in addition to what has been done in that phase 3 trial.
How should oncologists approach clinical decision-making when a phase 3 trial demonstrates a fragile, statistically significant result?
It is one of those circumstances where, for instance, when we think about clinical trials, we tend to fixate on certain statistical values. So, we often use the 0.05, the 5% significance cutoff, when determining if a trial is significant or not. I think the fragility of a clinical trial allows us to assess clinical trials in a different way. For a lot of people, it is hard to visualize what it means for a trial to have a P value of, say, 0.049 versus 0.01. Whereas, if you think about fragility, the way we are assessing it is by determining how many patients it takes to flip a result from significant to not significant. This provides a much better visual cue.
So, if you have a trial with 100 patients in each arm, and you just flip one patient's result, that could change the significance of the trial. I think it provides a much better visual picture than, say, a P value that barely attains that 0.05 threshold. What it means is that, if we see a fragile, statistically significant result, it suggests that we may want to design another trial—potentially a larger one with a bigger sample size—to ensure that what we're seeing is not just a statistical fluke. That way, we can make sure that a single patient, who may be an outlier, didn't tilt the results one way.
I would also say it depends on how the result is statistically fragile. Using the method that assesses fragility, we can flip patients who are the most average patients from one arm to the other. We can also flip the most extreme patients. When you flip the most extreme patients, it addresses the question of outliers. For example, if you have one major outlier in a group, and you're asking whether that outlier is responsible for the statistical significance of the trial, this method can help assess that. So, I think it does depend on how fragile the trial is, but certainly, if it only takes 1 or 2 patients to flip the result, it leads us to think we may need more patients and further investigation.
How important do you think long-term follow-up studies are for validating the results of phase 3trials?
I think they are extremely important, especially when looking at overall survival, because oftentimes, in terms of looking at surrogate end points, we can see that patients progress, but we have good therapies that allow them to have prolonged survival, even with progression. I think there is certainly no substitute for having a long-term follow-up and giving the time to see how patients do. I think the issue is that oftentimes we want to know the answers to questions quickly. Sometimes we do not have the luxury of waiting a decade or so to really see how the data plays out over time. But I do think it is important to, even if you have a positive result or a negative result initially, say at the 2- or 3-year mark, to still follow that up to 5 and 10 years, just to see if what we are seeing in the early stage is persistent and carries on to the later stages.
What strategies would you recommend for increasing the robustness of phase 3 trials in oncology?
I think the first thing is sample size. There is certainly no substitute for having a large sample size for these clinical trials. I think that can be challenging for certain types of cancers, especially rare cancers, or for clinical trials that address questions that are a little harder to sell to patients. It can be difficult to get enrollment, and it's always a constant challenge. Whenever we design phase 3 clinical trials in oncology, we always have a robust statistical analysis, and we work closely with our teams to design these trials. However, that is essentially in the theoretical realm. In the real world, what happens is, say, we have a trial that is powered to address a question with 500 patients, but oftentimes we are only able to enroll 100 or 200 patients. Because we enrolled these patients, we still want to know what the trial results show.
Sometimes, the trial results show a statistically significant result, but it ends up being a fragile result because the patient number was so small. It only takes a patient or two to change the statistical significance of the result. There is certainly no substitute for increasing the number of patients and trying to conduct large trials in the real world. Of course, it's not always possible, so we have to be careful about certain ways we analyze the data.
Crossover can certainly be a huge confounding factor when it comes to clinical trials, as it can skew the results. I would say, whenever we consider doing a crossover—often for ethical reasons, like when we know an arm is doing well, or patients request a certain arm—we do honor the request for crossovers, but we have to carefully track these patients and denote that it was a crossover. We should also analyze the data without the crossover, so do it both ways. Additionally, our results for clinical trials are often reported as intention –to treat, meaning patients are analyzed based on the arm they were originally randomized to. However, sometimes patients who were intended for one arm ended up in a different arm, and the intention-to-treat analysis doesn't always capture that. This aspect is very important, especially if a significant number of patients were not treated based on their initial randomization. That's another approach to decrease the fragility of trials and make the results more reproducible—by taking into account what intervention patients actually received.
As we know from fragility analysis, it sometimes doesn't take very many patients to change the outcomes. In terms of other things we can do to reduce the fragility of phase 3 trials, part of it comes down to conducting a good statistical analysis. Sometimes, the statistical tools we use aren't necessarily the best for analyzing the data. For instance, in many trials, we assume the proportional hazards assumption. However, when we look at the Kaplan-Meier curves, they sometimes cross over, which means the proportional hazards assumption is not met. In such cases, we need to use a different type of statistical analysis to correctly analyze the data. So, I think it's always very important for phase 3 trials to have a robust statistical team and to use the right type of analysis for these studies.
I think the biggest thing is that this fragility tool is not a substitute for the P value. The P value, the statistical significance, whether it is 0.05 or 0.01, is something well established, and I foresee it continuing to be the main factor we look at in the future when assessing clinical trials. However, this is another tool we can use in our toolbox.
In terms of clinical trials, it helps us visualize things much better than a P value, especially when we are talking to patients about certain trials. When we discuss the P value, it is a theoretical construct, whereas if we talk about fragility—like flipping patients from one arm to another—that is much easier to visualize and a good tool to use.
For trials with P values close to the cutoff, we can do a fragility analysis to see how fragile these trials are. If they are extremely fragile, we can consider adding more patients or extending the trial to ensure the results are validated and potentially less fragile. This applies to negative trials as well, because sometimes negative trials come close to the P value we are looking for. In those cases, we need to examine whether there were crossovers or if we are doing an intention-to-treat analysis where many patients did not receive the arm they were randomized to. This helps us assess, "What if these patients stayed on the arm they were supposed to be on? Would that influence the results?"
REFERENCE: Liu Y. The fragility of phase 3 trials in oncology. Abstract presented at: 2024 American Society for Radiation Oncology Annual Meeting; September 29-October 2, 2024; Washington, DC. Abstract 65267.Pharming Group Announces Start Of Phase II Clinical Trial Of Leniolisib For Primary Immunodeficiencies (PIDs) With Immune Dysregulation
Proof of concept clinical trial will evaluate leniolisib in PIDs with immune dysregulation linked to altered PI3Kẟ signaling in lymphocytes
PIDs to include ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN deficiency, with prevalence approximately five times that of APDS
Clinical trial being conducted at the National Institutes of Health (NIH)
Leiden, the Netherlands, October 10, 2024: Pharming Group N.V. ("Pharming" or "the Company") (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) announces the start of a Phase II, proof of concept, clinical trial evaluating leniolisib in primary immunodeficiencies (PIDs) with immune dysregulation linked to altered PI3Kẟ signaling in lymphocytes.
The clinical trial is open for enrollment and will include PID patients with ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN deficiency, among others. These PID patients exhibit altered PI3Kẟ signaling in lymphocytes and likewise display similar clinical phenotypes to activated phosphoinositide 3-kinase delta syndrome (APDS) patients. Epidemiology suggests a prevalence of approximately seven patients per million in this targeted PID population, compared to one to two patients per million for APDS.
The Phase II clinical trial is a single arm, open-label, dose range-finding study to be conducted in approximately 12 patients. The objectives for the trial will be to assess safety and tolerability, pharmacokinetics, pharmacodynamics, and explore clinical efficacy of leniolisib in the targeted PID population. The trial has been designed to inform a subsequent Phase III program. The Phase II clinical trial is being conducted at the National Institute of Allergy and Infectious Diseases (NIAID) – part of the National Institutes of Health (NIH) – with lead investigator Gulbu Uzel, M.D., Senior Research Physician, and co-investigator V. Koneti Rao, M.D., FRCPA, Senior Research Physician, Primary Immune Deficiency Clinic (ALPS Clinic).
Anurag Relan, MD, MPH, Chief Medical Officer of Pharming, commented:"The initiation of this study is an important milestone for Pharming as it represents the second primary immunodeficiency (PID) clinical program for leniolisib. Based on our experience in APDS, and the significant role of PI3Kd in regulating lymphocytes, leniolisib has the potential to address the underlying immune dysregulation and deficiency in a number of rare PID disorders with significant unmet medical needs, including ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN deficiency. We are excited to be leading this important scientific effort and to sharing the results of the study with the medical community."
The first patient is expected to be enrolled in the study in the coming weeks.
This is the first clinical trial initiated by Pharming to study leniolisib in PIDs with immune dysregulation beyond APDS. The unique genetic drivers in ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN patients lead to enhanced PI3Kd signaling and clinical phenotypes of immune dysregulation shared with APDS. Specifically, PTEN patients with immunodeficiency are frequently described as 'APDS-like'1, patients with ALPS-FAS display predominantly lymphoproliferative clinical manifestations with frequent cytopenic episodes2, and CTLA4 haploinsufficiency3 as well as NFKB1 haploinsufficiency4 patients demonstrate lymphoproliferative, cytopenic, and/or organ-specific autoimmune/inflammatory complications of immune dysregulation.
Leniolisib is marketed in the U.S. And approved in several other countries, for the treatment of APDS in adult and pediatric patients 12 years of age and older.
About leniolisibLeniolisib is an oral small molecule phosphoinositide 3-kinase delta (PI3Kẟ) inhibitor approved in the U.S. And several other countries as the first and only targeted treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. Leniolisib inhibits the production of phosphatidylinositol-3-4-5-trisphosphate, which serves as an important cellular messenger and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism. Results from a randomized, placebo-controlled Phase III clinical trial demonstrated statistically significant improvement in the coprimary endpoints, reflecting a favorable impact on the immune dysregulation and deficiency seen in these patients, and interim open label extension data has supported the safety and tolerability of long-term leniolisib administration.5,6 Leniolisib is currently under regulatory review in the European Economic Area, Canada and Australia for APDS, with plans to pursue further regulatory approvals in Japan and South Korea. Leniolisib is also being evaluated in two Phase III clinical trials in children with APDS and in a Phase II clinical trial in primary immunodeficiencies (PIDs) with immune dysregulation linked to altered PI3Kẟ signaling in lymphocytes. The safety and efficacy of leniolisib has not been established for PIDs with immune dysregulation beyond APDS.
About Pharming Group N.V. Pharming Group N.V. (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) is a global biopharmaceutical company dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. Pharming is commercializing and developing an innovative portfolio of protein replacement therapies and precision medicines, including small molecules and biologics. Pharming is headquartered in Leiden, the Netherlands, and has employees around the globe who serve patients in over 30 markets in North America, Europe, the Middle East, Africa, and Asia-Pacific.
For more information, visit www.Pharming.Com and find us on LinkedIn.
Forward-Looking Statements This press release may contain forward-looking statements. Forward-looking statements are statements of future expectations that are based on management's current expectations and assumptions and involve known and unknown risks and uncertainties that could cause actual results, performance, or events to differ materially from those expressed or implied in these statements. These forward-looking statements are identified by their use of terms and phrases such as "aim", "ambition", ''anticipate'', ''believe'', ''could'', ''estimate'', ''expect'', ''goals'', ''intend'', ''may'', "milestones", ''objectives'', ''outlook'', ''plan'', ''probably'', ''project'', ''risks'', "schedule", ''seek'', ''should'', ''target'', ''will'' and similar terms and phrases. Examples of forward-looking statements may include statements with respect to timing and progress of Pharming's preclinical studies and clinical trials of its product candidates, Pharming's clinical and commercial prospects, and Pharming's expectations regarding its projected working capital requirements and cash resources, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Pharming's clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory, commercial, competitive and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in Pharming's 2023 Annual Report and the Annual Report on Form 20-F for the year ended December 31, 2023, filed with the U.S. Securities and Exchange Commission, the events and circumstances discussed in such forward-looking statements may not occur, and Pharming's actual results could differ materially and adversely from those anticipated or implied thereby. All forward-looking statements contained in this press release are expressly qualified in their entirety by the cautionary statements contained or referred to in this section. Readers should not place undue reliance on forward-looking statements. Any forward-looking statements speak only as of the date of this press release and are based on information available to Pharming as of the date of this release. Pharming does not undertake any obligation to publicly update or revise any forward-looking statement as a result of new information, future events or other information.
References
For further public information, contact:Pharming Group, Leiden, the NetherlandsMichael Levitan, VP Investor Relations & Corporate CommunicationsT: +1 (908) 705 1696E: investor@pharming.Com
FTI Consulting, London, UKVictoria Foster Mitchell/Alex Shaw/Amy ByrneT: +44 203 727 1000
LifeSpring Life Sciences Communication, Amsterdam, the NetherlandsLeon MelensT: +31 6 53 81 64 27E: pharming@lifespring.Nl
US PRChristina RenfroeT: +1 (636) 352-7883E: Christina.Renfroe@precisionaq.Com
Pfizer's TALZENNA® In Combination With XTANDI® Prolongs Overall Survival In Phase 3 TALAPRO-2 Trial
NEW YORK--(BUSINESS WIRE)--Pfizer Inc. (NYSE: PFE) today announced positive topline results from the final prespecified overall survival (OS) analysis of the TALAPRO-2 study of TALZENNA® (talazoparib), an oral poly ADP-ribose polymerase (PARP) inhibitor, in combination with XTANDI® (enzalutamide), an androgen receptor pathway inhibitor (ARPI), in patients with metastatic castration-resistant prostate cancer (mCRPC). Results showed a statistically significant and clinically meaningful improvement in the final OS in all-comers (cohort 1) as well as in those patients with homologous recombination repair (HRR) gene-mutated mCRPC (cohort 2), compared to XTANDI alone.
"The TALAPRO-2 results showed that TALZENNA plus XTANDI is the first and only PARP inhibitor in combination with an ARPI to significantly improve survival in patients with metastatic castration-resistant prostate cancer, regardless of mutation status," said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer. "Pfizer is dedicated to advancing scientific breakthroughs in genitourinary cancers, and these exciting TALAPRO-2 results further highlight our long-standing commitment to improving survival for men with prostate cancer."
"These overall survival results indicate potentially practice-changing efficacy for TALZENNA in combination with XTANDI for men with metastatic castration-resistant prostate cancer," said Neeraj Agarwal, M.D., FASCO, Professor and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, and global lead investigator for TALAPRO-2. "Metastatic castration-resistant prostate cancer is the most advanced and aggressive stage of the disease, and the TALAPRO-2 results provide much-needed hope to patients who remain in high unmet need for effective treatment options."
At the time of the final analysis, the clinically meaningful improvement in radiographic progression free survival (rPFS) was maintained in both cohorts from the prior primary analysis previously reported and published in The Lancet. In addition, the safety profile of TALZENNA plus XTANDI was generally consistent with the known safety profile of each medicine. Detailed results from TALAPRO-2 will be submitted for presentation at an upcoming medical congress. These data will also be shared with global health authorities to potentially support regulatory filings to update and potentially expand the approved label for TALZENNA.
TALZENNA in combination with XTANDI was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with HRR gene-mutated mCRPC in June 2023. The combination was also approved by the European Commission in January 2024 for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated. TALZENNA is the first and only PARP inhibitor licensed in the European Union for use with XTANDI for patients with mCRPC, with or without gene mutations. TALZENNA in combination with XTANDI is now approved in more than 35 countries globally for patients with mCRPC.
About Metastatic Castration-Resistant Prostate Cancer
Prostate cancer is the second most common cancer in men and the fifth most common cause of cancer death among men worldwide, with an estimated 1.4 million new cases diagnosed in 2022.1 In the U.S., it is the most common cancer in men.2 mCRPC is a cancer that has spread beyond the prostate gland and has progressed despite medical or surgical treatment to lower testosterone. Approximately 10%–20% of prostate cancer patients develop mCRPC within 5−7 years of diagnosis.3 Between 1.2%–2.1% of all prostate cancer cases globally are mCRPC.4
About TALAPRO-2
The Phase 3 TALAPRO-2 trial is a multicenter, randomized, double-blind, placebo-controlled study that enrolled 1,035 unique patients with mCRPC (who had not received new life-prolonging systemic treatments after documentation of mCRPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: all-comers (n=805, of whom 169 had HRR mutations and 636 did not) and those with HRR gene mutations (n=399, including 169 patients from Cohort 1 and 230 enrolled in Cohort 2). Patients with castrate testosterone levels were randomized to receive TALZENNA 0.5 mg/day plus XTANDI 160mg/day, or placebo plus XTANDI 160mg/day.
The primary endpoint of the trial was rPFS, defined as the time from the date of randomization to first objective evidence of radiographic progression by blinded independent review, or death, whichever occurred first, in both Cohort 1 (all-comers) and Cohort 2 (those with HRRm). Secondary endpoints included OS, objective response rate (ORR), duration of response (DOR), and prostate-specific antigen (PSA) response.
For more information on the TALAPRO-2 trial (NCT03395197), go to www.Clinicaltrials.Gov.
About TALZENNA® (talazoparib)
TALZENNA is an oral inhibitor of poly ADP-ribose polymerase (PARP), which plays a role in DNA damage repair. Preclinical studies have demonstrated that TALZENNA blocks PARP enzyme activity and traps PARP at the site of DNA damage, leading to decreased cancer cell growth and cancer cell death.
TALZENNA is approved in the U.S., EU, and multiple other regions for the treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2-negative locally advanced or metastatic breast cancer. In the U.S., TALZENNA is approved in combination with XTANDI for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). In the EU, TALZENNA is approved in combination with enzalutamide for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated.
TALZENNA®(talazoparib) Indication in the U.S.
TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for:
HRR gene-mutated mCRPC:
Breast Cancer:
TALZENNA®(talazoparib) Important Safety Information
WARNINGS and PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with a fatal outcome, has been reported in patients who received TALZENNA. Overall, MDS/AML has been reported in 0.4% (3 out of 788) of solid tumor patients treated with TALZENNA as a single agent in clinical studies. In TALAPRO-2, MDS/AML occurred in 2 out of 511 (0.4%) patients treated with TALZENNA and enzalutamide and in 0 out of 517 (0%) patients treated with placebo and enzalutamide. The durations of TALZENNA treatment in these five patients prior to developing MDS/AML were 0.3, 1, 2, 3, and 5 years, respectively. Most of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.
Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Monitor blood counts monthly during treatment with TALZENNA. For prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If counts do not recover within 4 weeks, refer the patient to a hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA.
Myelosuppression consisting of anemia, neutropenia, and/or thrombocytopenia have been reported in patients treated with TALZENNA. In TALAPRO-2, Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 45%, 18%, and 8% of patients receiving TALZENNA and enzalutamide. Overall, 39% of patients (199/511) required a red blood cell transfusion, including 22% (111/511) who required multiple transfusions. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 7%, 3%, and 0.4% of patients.
Withhold TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. Monitor blood counts monthly during treatment with TALZENNA. If hematological toxicities do not resolve within 28 days, discontinue TALZENNA and refer the patient to a hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics.
Embryo-Fetal Toxicity TALZENNA can cause fetal harm when administered to pregnant women. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with TALZENNA and for 4 months after receiving the last dose.
ADVERSE REACTIONS
In TALAPRO-2, serious adverse reactions reported in >2% of patients included anemia (9%) and fracture (3%). Fatal adverse reactions occurred in 1.5% of patients, including pneumonia, COVID infection, and sepsis (1 patient each).
The most common adverse reactions (≥ 10%, all Grades), including laboratory abnormalities, for patients in the TALAPRO-2 study who received TALZENNA in combination with enzalutamide vs patients receiving placebo with enzalutamide were hemoglobin decreased (79% vs 34%), neutrophils decreased (60% vs 18%), lymphocytes decreased (58% vs 36%), fatigue (49% vs 40%), platelets decreased (45% vs 8%), calcium decreased (25% vs 11%), nausea (21% vs 17%), decreased appetite (20% vs 14%), sodium decreased (22% vs 20%), phosphate decreased (17% vs 13%), fractures (14% vs 10%), magnesium decreased (14% vs 12%), dizziness (13% vs 9%), bilirubin increased (11% vs 7%), potassium decreased (11% vs 7%), and dysgeusia (10% vs 4.5%).
Clinically relevant adverse reactions in <10% of patients who received TALZENNA with enzalutamide included abdominal pain (9%), vomiting (9%), alopecia (7%), dyspepsia (4%), venous thromboembolism (3%) and stomatitis (2%).
Based on animal studies, TALZENNA may impair fertility in males of reproductive potential.
DRUG INTERACTIONS
Coadministration with P-gp inhibitors The effect of coadministration of P-gp inhibitors on talazoparib exposure when TALZENNA is taken in combination with enzalutamide has not been studied. Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a P-gp inhibitor.
Coadministration with BCRP inhibitors Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a BCRP inhibitor. Coadministration of TALZENNA with BCRP inhibitors may increase talazoparib exposure, which may increase the risk of adverse reactions.
USE IN SPECIFIC POPULATIONS
Renal Impairment The recommended dosage of TALZENNA for patients with moderate renal impairment (CLcr 30 - 59 mL/min) is 0.35 mg taken orally once daily in combination with enzalutamide. The recommended dosage of TALZENNA for patients with severe renal impairment (CLcr 15 - 29 mL/min) is 0.25 mg taken orally once daily in combination with enzalutamide. No dose adjustment is required for patients with mild renal impairment. TALZENNA has not been studied in patients requiring hemodialysis.
Please see full U.S. Prescribing Information and Patient Information for TALZENNA® (talazoparib) at www.TALZENNA.Com.
About XTANDI® (enzalutamide) and Important Safety Information
XTANDI® (enzalutamide) is an androgen receptor signaling inhibitor. XTANDI is a standard of care and has received regulatory approvals in one or more countries around the world for use in men with metastatic castration-sensitive prostate cancer (mCSPC; also known as metastatic hormone-sensitive prostate cancer or mHSPC), metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC) and nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). XTANDI is currently approved for one or more of these indications in more than 90 countries, including in the U.S., EU, and Japan. Over one million patients have been treated with XTANDI globally.5
Warnings and Precautions
Seizure occurred in 0.6% of patients receiving XTANDI in eight randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer's disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.
Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in eight randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.
Ischemic Heart Disease In the combined data of five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on XTANDI versus 1.1% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.
Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Fractures occurred in 13% of patients treated with XTANDI and in 6% of patients treated with placebo.
Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI.
Adverse Reactions (ARs) the data from the five randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.
In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to ARs were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to ARs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AR as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.
In PROSPER, the placebo-controlled study of nonmetastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AR as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.
In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher ARs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to ARs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.
In EMBARK, the placebo-controlled study of nonmetastatic CSPC (nmCSPC) with high-risk biochemical recurrence (BCR) patients, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide.
Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are hemoglobin decrease, neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, hyperphosphatemia, and hypercalcemia.
Hypertension: In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14.2% of XTANDI patients and 7.4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.
Drug Interactions
Effect of Other Drugs on XTANDI Avoid coadministration with strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI.
Avoid coadministration with strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI.
Effect of XTANDI on Other Drugs Avoid coadministration with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which minimal decrease in concentration may lead to therapeutic failure of the substrate. If coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.
Please access this link for XTANDI'S US Full Prescribing Information for additional safety information.
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world's most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives.
About Pfizer: Breakthroughs That Change Patients' Lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development, and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments, and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments, and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.Com. In addition, to learn more, please visit us on www.Pfizer.Com and follow us on X at @Pfizer and @Pfizer News, Li
Comments
Post a Comment