Parp inhibitor trial failure

I continue to see Dr. Hosein regularly and I keep Dr. Every other month I travel from south Florida to Philadelphia to get treatment in the clinical trial.

I was scheduled to travel to Philadelphia to see Dr. Reiss Binder in March for my clinical trial visit and lab work. But due to the risk of the coronavirus, the clinical trial team decided to ship me the rucaparib and scheduled a telemedicine visit with Dr. Reiss Binder rather than have me travel. We will repeat this protocol for my next clinical trial visit in May It does indeed take a team of specialists to figure everything out and to help patients take the best next steps.

I have been fortunate to have the companionship of wonderful family and friends to support me through this journey. My Treatment. I am 73 years old and I was diagnosed with stage IIb pancreatic cancer in mid-June Related Stories.

Tomorrow Is a New Day. In this regard, niraparib has shown in preclinical studies higher trapping potency and deeper cell penetration. In addition, recent papers discussed how trapping can play a role to explain efficacy beyond BRCA mutation. This can explain differences in terms of allosteric DNA binding and activity. However, the potential risks of PARP inhibitor therapy have to be balanced with the relatively modest benefit.

Unfortunately, none of the trials reports strong evidence, and as the statistical analyses were exploratory further trials are needed to resolve the question of what should be the best first-line maintenance therapy for HRD-negative tumours.

Both bevacizumab and niraparib can be considered as maintenance therapy options in patients harbouring HRp tumours.

Due to the modest effect of PARP inhibitors in HR-proficient patients and their poorer prognosis, there is an urgent need for new treatment strategies in this patient subgroup.

However, the magnitude of benefit is clearly inferior than in other subgroups. Therefore, based on these results, niraparib maintenance therapy is indicated for all patients with high-grade ovarian cancer in response to first-line therapy supported by the FDA and EMA approval. How many more patients is niraparib able to keep free of progression at the threshold of 6 months from the last dose of platinum compared with placebo?

Moreover, numerically, the median PFS was 8. The relevant difference with the ICON7 trial is that patients were randomised before starting chemotherapy. The HR of 0. As a matter of discussion with these patients, carboplatin in combination with paclitaxel plus bevacizumab as first-line therapy should be considered mainly for patients who also present high-risk clinical characteristics, that is, suboptimally debulked, stage IV and no debulking surgery, as was the population enrolled in the PRIMA trial.

Despite clinical trial results reporting the efficacy of bevacizumab beyond progression, 23 in many countries not in the USA it is not possible to further use bevacizumab in patients who have previously received bevacizumab. These limitations in prescribing should be taken into account when considering the treatment algorithm.

When a clear benefit of the combination of a PARP inhibitor plus bevacizumab is not evident, as in patients with HRD-negative tumours, or for example if bevacizumab is not feasible in the first line, a possible strategy is to consider the sequential use of maintenance therapies, using PARP inhibitors in first line considering the necessity of platinum response to prescribe PARP inhibitors which decreases over time in later lines , and delay the use of bevacizumab to the time of recurrence, either in the platinum-resistant or platinum-sensitive setting, where a significant benefit has also been reported HR 0.

However, decisions should be individualised and take into consideration the licensed indication, which may include high-grade histologies. There is no effective biomarker for excluding the benefit of PARP inhibitor maintenance therapy in HRD-negative-proficient patients who are not receiving bevacizumab. Two assays have been developed to measure genomic instability 25 :. Nevertheless, better identification of patients with HR-proficient tumours is a priority. A more robust HRD test needs to be developed for successful integration in clinical practice.

It is a challenge which requires expertise in molecular profiling, bioinformatics and biostatistics in order to address the panel genes of the genomic scars involved in the HRD mechanisms and clinical validation. This opportunity should not be missed. There are no data showing a survival benefit by close and intensive follow-up compared with less intensive follow-up. However, regular assessment is recommended to monitor the toxicity and efficacy of maintenance therapy, including evaluation of symptoms suggesting relapsed disease.

Further investigations CA and imaging should be carried out according to national guidelines for follow-up. In patients with AOC, most recurrences occur during the first 3 years after completion of first-line chemotherapy.

Therefore, the ideal maintenance treatment should perhaps at least cover the period of maximum risk of relapse. These data raise the question of whether prolonged duration of treatment may play a role in further reducing progression events and impacting on survival. In recurrent ovarian cancer, maintenance PARP inhibitors are continued until disease progression.

The median OS improved by It is possible that different molecular subgroups, which gain different magnitudes of benefit from maintenance treatment, may benefit from differential maintenance durations.

Long-term safety data of PARP inhibitors, particularly in terms of severe adverse events AE such as acute AML and MDS and quality of life, will further inform the optimal length of duration for a well-balanced risk:benefit ratio. After first-line platinum-based chemotherapy, PARP inhibitors should be maintained for at least 2 years olaparib or 3 years niraparib to cover the period of maximum risk of recurrence.

The question of whether different molecular subgroups may benefit from different maintenance therapy durations needs to be addressed. Clinicians, nurses and patients need to be aware of class-specific and drug-specific toxicities and how to manage them.

Class-specific AEs include anaemia, fatigue and nausea, which are common in all available PARP inhibitors; others are more typical of specific agents, that is, thrombocytopaenia and hypertension for niraparib and transaminases elevation for rucaparib. Individualised niraparib starting dosing according to baseline body weight and platelet count has been reported to decrease toxicity without significantly impacting on treatment efficacy, 31 32 and this strategy should be routinely implemented in clinical practice.

Most PARP inhibitor toxicities are manageable with dose reductions and dose interruptions. Permanent discontinuations due to unmanageable toxicity should be considered only when dose reduction or interruptions have failed. With current approvals for PARP inhibitors in the recurrent disease setting, excluding women who previously received a PARP inhibitor, 33 other postprogression approaches need to be considered for patients in recurrence following maintenance PARP inhibitor therapy.

While there are data that retreatment with bevacizumab is beneficial, 23 34 there are so far no data for retreatment with a PARP inhibitor with regard to efficacy and safety. It is likely that there are biological differences given the mechanisms of PARP inhibitor resistance, including the development of secondary mutations. The development of liquid biopsies to study PARP inhibitor resistance would be helpful.

However, as patients who underwent surgery on relapse were also included in the maintenance PARP inhibitor and bevacizumab trials in relapsed disease, 19 20 30 36 there is no evidence to withhold maintenance therapy if this remains an option. Given the increasing patient population receiving first-line PARP inhibitors, the development of new agents and strategies for treatment post progression following a PARP inhibitor is urgently needed. The trial, called OlympiA , showed that people who received olaparib had a 42 percent reduction in risk of breast cancer recurrence compared to those who received a placebo.

Nearly 86 percent of those given olaparib for a year after treatment saw no return, relapse, or spread of their breast cancer three years later, compared with Reiss, M. Some of that data comes from the POLO trial. This phase III study tested olaparib compared to placebo in patients with germline BRCA mutations and platinum-sensitive, metastatic pancreatic cancer, Reiss explains.

POLO demonstrated that patients had significantly longer progression-free survival with maintenance olaparib than with a placebo. In this second study, patients had a six-month progression-free survival of The overall response rate of Two-thirds of patients obtained disease control with the PARP inhibitor.

Several trials have come along examining the use of PARP inhibitors in the frontline treatment of recurrent ovarian cancer, but data are more limited when it comes to retreatment with PARP or what to do in those who develop acquired resistance to these agents. While there currently is no optimal strategy to overcome PARP resistance, methods such as repairing double-strand breaks by recovering homologous recombination proficiency, utilizing antiangiogenic agents, such as cediranib or bevacizumab Avastin , and combining PARP inhibitors with immunotherapy are all possible options, added Konecny.

Konecny : The addition of PARP inhibitors to the treatment of patients with early-stage ovarian cancer and recurrent disease has made a very large impact on improving PFS. Despite these successes, unfortunately, many patients face [progression on] these drugs over time. That leads us to focus on mechanisms of drug resistance and understanding how we can overcome these mechanisms of drug resistance.

About half of all ovarian cancers have an intrinsic primary drug resistance to PARP inhibitors, as they have a competent high-fidelity double-strand break repair mechanism that's intact. Single-strand break repair disruption through a PARP inhibitor is not that relevant in these cases because the backup DNA repair mechanism steps in and the drug does not work through synthetic lethality in these patients. Of those patients who are initially deficient of double-strand break repair, we now understand that many patients can develop resistance by a recovery of double-strand break repair.

That means recovery of homologous recombination, and this is due to demethylation of 1 of the silenced BRCA1 genes. It has also been described by an increase in copy numbers that occur during disease progression of either mutated or unmutated BRCA allele, which leads to an increased expression of the protein.

This is basically alternative splicing of a hypomorphic BRCA1; that's particularly pertaining to exon 11, so if mutations are in exon 11, it can be that some of these cell clones splice out the mutation and they have restoration of homologous recombination. Then, there is a large area where negative regulators of homologous recombination can be lost, and there is loss of negative regulators are basically involving the proteins 53BP1 or REV7.

Beyond that, PARP inhibitors have shown to be effective by leading to the replication for degradation; PARP inhibitors also function not just through enzymatic inhibition of PARylation and recruiting DNA repair factors, but they blocks the replication fork and leads to its degradation.

There are a number of proteins that execute this degradation, and when you lose these executers that are supposed to complete the command of destroying the replication, then PTIP, MRE11, or EZH2 can also be lost.

Therefore, a PARP inhibitor loses its ability to degrade the replication fork and gets less effective. Lastly, there are mechanisms, such as drug efflux pumps that just simply decrease the intracellular drug concentrations by pumping the drug out efficiently through the well-described P-glycoprotein pump, which is also responsible for chemotherapy resistance in many instances.

Currently, we don't have a good understanding of how clinically relevant these described mechanisms are.