Rapid spread of Corona Virus Disease (COVID-19) has dramatically impacted the oncology care and Dr. Reddy’s in this time is committed to accelerate the access to affordable and innovative medicines as well as sharing the insights among the thought leaders. With this aim, webinar on the topic “Choosing Systemic Treatment for Advanced Prostate Cancer in the COVID times” was organized by Dr. Reddy’s Laboratories Limited on May 12th and 19th, 2020 respectively. The webinar was hosted by Dr. Deepak on behalf of Dr. Reddy’s Medical Affairs Team with over 300 oncologists, clinical oncologists and urologists onboard from Brasil, Colombia, Chile, Jamaica, Trinidad and Tobago, Barbados, Malaysia, Thailand, Vietnam, Myanmar, and South Africa.
Webinar 1: 12th May 2019
Key Note Speaker: Prof Karim Fizazi, MD, PhD Head of the Department of Cancer Medicine at Institute Gustave Roussy; Professor of Medicine at the University of Paris Sud. Prof. Fizazi is the President of the French Groupe d’Etude des Tumeurs Genito-Urinaires (GETUG) & French Study Group of Carcinomas of Unknown Primary (GEFCAPI). He is the founder of Prostate Cancer Consortium in Europe (PEACE); Associate editor of European Journal of Cancer and consulting editor of European Urology. He has authored more than 350 peer-reviewed articles.
Chairperson: Dr. Andrey Soares, Scientific Director LACOG (Latin American Cooperative Oncology Group) Brasil
Dr. Deepak CSN– Medical Affairs Team, Dr. Reddy’s Laboratories, India
Webinar 2: 19th May 2019
Key Note Speaker: Dr. Karim Fizazi – Head of the Department of Cancer Medicine at Institut Gustave Roussy, Villejuif, France
Co-chairperson: Professor Teng Aik Ong – Vice President Malaysian Urological Association, Head of Division of Urology at University of Malaya, Malaysia
Co-chairperson: Dr. Malwinder Singh– Consultant Clinical Oncologist, Sri Kota Specialist Medical Centre, Malaysia
Dr. Deepak CSN – Dr. Reddy’s Laboratories, India
Welcome Message from the Host
Dr. Deepak welcomed chairperson and Prof. Fizazi, explained objectives of meeting in brief and handed over the session to chairperson(s).
Key Messages from the Webinar
- TMPRSS2 and COVID-19: TMPRSS2 is a special gene of interest in prostate cancer, approximately 50% of those having prostate cancer are found to have fusion genes present between TMPRSS2 (related to androgen receptor; AR axis) and oncogene ERG or another oncogene of ETS family.
- The TMPRSS2-ERG fusion results in the overexpression of ERG protein pushing the cancer to proceed forward (cancer progression).
- TMPRSS2 is also important for COVID-19.
- The COVID virus needs to bind to some proteins like ACE2 for cell entry: entry of SARS-CoV-2 depends on binding of the viral spike (S) proteins to ACE2 and on S protein priming by TMPRSS2, which in turn is regulated by the AR protein.
- Theoretically speaking if we are targeting TMPRSS2 (that could be done) through AR axis inhibitors, then we might be able to prevent patients from getting infected (prevent infection).
- The demonstration of this could be seen from analysis of Italian patients’ data- suggesting a potential protective role of androgen deprivation therapy (ADT) against SARS-CoV-2 infection.
- Androgen deprivation therapy (ADT) is protective of COVID-19: Preliminary data from Italy suggested that the prostate cancer patients on ADT have 4 times less risk of COVID-19 infection and developing serious disease (OR: ~ 4, 95% CI: 1.55-10.59; P: 0.0059).
- Systemic treatment options for advanced prostate cancer are as follow:
- M0 CRPC: Darolutamide, Apalutamide, Enzalutamide
- Metastatic Castration-Sensitive Prostate Cancer (mCSPC): ADT + Abiraterone, ADT + Docetaxel or ADT
- Metastatic Castrate-Resistant Prostate Cancer (CRPC): Abiraterone, Enzalutamide, Docetaxel, Denosumab, and Radium 223, Cabazitaxel
Strategies for Treating Advanced Prostate Cancer
- Using chemotherapy immediately together with castration will make patients with de novo metastatic prostate cancer do better compared to using ADT alone.
- Four trials (CHAARTED, GETUG15, STAMPEDE (standard of care [SOC] + Docetaxel), STAMPEDE (SOC + Zoledronic Acid [ZA] + Docetaxel) showed improvement in survival with Docetaxel. Overall 23% reduction in the risk of death when Docetaxel + SOC used upfront but in reality, the benefit is < 20>
- Phase III trials with Abiraterone (LATTITUDE and STAMPEDE): Abiraterone improved overall survival (OS) in metastatic mCSPC with benefit started showing up 6 months after randomization.
- Better outcomes with Abiraterone: Median OS and median time to pain (TTP) was found to be better with Abiraterone when compared with placebo (53.3 months vs. 36.5 months and 47.4 months vs. 16.6 months, respectively) in M1 CSPC.
- Quality of Life (QoL) parameters improved with Abiraterone: Abiraterone showed clear advantage over placebo in improving the General Health Status and the EQ-5D-5L Health Utility Score. It is rare to find such differences in QoL between 2 arms.
- Phase III trial (PEACE 1): Question arises as to whether we should combine Docetaxel and Abiraterone together; this can be answered with the PEACE-1 trial. This is a randomized multi-center phase III study to compare the clinical benefit of ADT (+ Docetaxel) with or without local radiotherapy with or without Abiraterone acetate and Prednisone in patient with metastatic hormone-naïve prostate cancer. Accrual is completed.
- Long-term treatment with a low dose of corticosteroids with Abiraterone is associated with low overall incidence of corticosteroid-associated adverse events (CA-AEs). The frequency of CA-AEs remained low with increased duration of exposure.
- Use of corticosteroids and Non-steroid Anti-Inflammatory Drugs (NSAIDS): It is advisable that one has to be wary of using corticosteroids and NSAIDS when infected with COVID-19.
- There appeared to be some evidence that corticosteroids may be beneficial if utilized in the early acute phase of infection, however, conflicting evidence from the World Health Organization (WHO) encompassing corticosteroid use in certain viral infections means this evidence is not conclusive.
- Given the current availability of literature, caution should be exercised until further evidence emerges on the use of NSAIDs and corticosteroids in COVID-19 patients. However recent data seems more reassuring and more data shall emerge.
- Hormonal therapies or Docetaxel for M1 CSPC: Post-hoc analysis suggested that ADT + Abiraterone did exceedingly well than ADT + Docetaxel in terms of failure free survival.
- Abiraterone Acetate (AA) + Prednisone + ADT are associated with an improved QoL compared with Docetaxel + ADT in metastatic hormone-sensitive prostate cancer (mHSPC).
- Prostate radiotherapy de-novo metastatic disease (M1): Radiation therapy resulted in improvement of OS in men with oligo-metastatic disease as compared to ADT and hence should be used in patients with larger burden of the disease.
- Current treatment options for de-novo metastatic disease (M1) are as follows:
- ADT + Abiraterone should be the choice of treatment
- Radiation therapy for oligo metastatic disease
- ADT + Docetaxel only if Abiraterone is not available
- ADT alone for frail and very elderly patients
- Availability of Abiraterone generics: An informal survey suggested that generics are available in most parts of the world now making the treatment more accessible and cheaper.
- SPARTAN, PROSPER, and ARAMIS phase III trials for M0CRPC treatment: Apalutamide, Enzalutamide, and Darolutamide favors the metastasis free survival and OS improvement.
Sequential Treatment in mCRPC
- Although sequential use of AR axis targeted agents is not suggested, but it has been shown that Abiraterone followed by Enzalutamide seems to be a better approach than Enzalutamide followed by Abiraterone both in terms of OS and PFS.
- Retrospective data suggest that men with failed Abiraterone therapy showed improvement with Docetaxel post Abiraterone therapy.
- CARD phase III study (to answer whether sequential hormone treatment should be used instead of Taxane): Cabazitaxel improved clinical outcomes, as compared with the androgen-signaling–targeted inhibitor (Abiraterone or Enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with Docetaxel and the alternative androgen-signaling–targeted agent (Abiraterone or Enzalutamide).
- Cancer patients and Covid-19 at Gustave Roussy: ECOG performance status, cancer type, and type of prior therapy received can predict risk for clinical worsening or death in patients with cancer who contract the COVID-19.
- ECOG performance status greater than 1 was a predictor of clinical worsening in patients with the virus on univariate analysis (HR, 4.6; 95% CI, 2.2-10.0; P <.0001). Additionally, patients with hematologic malignancies also had a higher risk for deterioration than those with solid tumors on univariate analysis (HR, 2.7; 95% CI, 1.3-5.5; P = .008).
- Chemotherapy in the last 3 months was also found to be associated with worst outcome in comparison to those who did not receive any chemotherapy in the last 3 months.
- Targeted and immune therapy did not result in any clinical deterioration among patients diagnosed with COVID-19.
- However, the factor predictive of death in multivariate analyses of OS was ECOG performance status greater than 1 (HR, 3.4; 95% CI, 1.2-9.8).
- Before using chemotherapy, benefit-risk analysis should be made during COVID times.
Combination Therapy for CRPC
- The ERA223 trial randomized 806 patients with chemotherapy-naïve, mCRPC with bone metastasis to radium-223 or placebo, in addition to abiraterone acetate. Symptomatic skeletal event-free survival was the primary outcome. The trial was unblinded prematurely as more fractures and deaths were identified in the radium-223 arm than among patients receiving placebo.
- Subsequently, question of whether mandated use of bone protecting agents, Zoledronic acid or denosumab, would have mitigated the fracture risk was assessed in PEACE 3 study.
- A randomized phase III open label trial (PEACE 3) to assess if upfront combination of enzalutamide and Ra223 improves radiological progression-free survival compared to Enzalutamide single agent in asymptomatic or mildly symptomatic CRPC patients metastatic to bone.
- Risk of fracture before and after the protocol amendment reveals combination of bone protecting agents (BPA) with Enzalutamide and/or Ra223 effectively reduces the cumulative incidence function of the fracture after 2 years of treatment compared with Enzalutamide or Enzalutamide-radium combination.
- The results emphasize the importance of treating mCRPC patients with bone protective agents when using Abiraterone or Enzalutamide.
- Additionally, bone-protecting agents, Zoledronic acid and Denosumab reduces the spinal cord compression by 4% and 2.7%; respectively, compared to 8% with placebo.
Personalized treatments: New Targets for CRPC
- CRPC can develop through reactivation of AR pathway.
- Phosphatase and tensin (PTEN) activates PI3K, which is a potential target for the treatment.
- Deoxyribonucleic acid (DNA) repair defect is more appealing potential target for treatment.
- Testosterone and dihydrotestosterone (DHT) are the main hormones that bind to ARs which can be managed by castration. Androgen made by adrenals can also bind to ARs.
- Although, Abiraterone can prevent this binding but with the disease progression some amount of androgen is found in the cells. So, it is very important to inhibit the hormone production .
- Because ARs are activated by nine other androgen hormones, we might need to stop making of all these hormones downstream of cholesterol pathway by drugs such as ODM-208, ODM-209 (UNDER PHASE I).
- Loss of PTEN activates the mammalian target of rapamycin (mTOR) and AR pathway. Although it is reported to occur in fewer men, it is necessary to target both AR pathway and PI3K-Akt pathway.
- In patients with PTEN loss, combined blockade with Abiraterone and Ipatasertib showed superior antitumor activity, this study is the first to demonstrate that the combination of Ipatasertib and Abiraterone is superior to abiraterone alone, delaying radiographic progression free survival (rPFS) particularly in mCRPC with PTEN loss.
- DNA repair and prostate cancer: Approximately 12% men with prostate cancer have germline mutation mostly in BRACA2, while 10% have somatic mutation.
- Treatment with Poly (ADP-ribose) polymerase (PARP) inhibitor, Oliaparib in metastatic (mCRPC) patients, who had disease progression while receiving Enzalutamide or Abiraterone showed significantly longer imaging-based PFS.
- DNA damage responsive (DDR) genes such as BRCA2, CDK12 are good target for treatment with Olaparib. Few other genes are under phase III trial.
- Most phase III immunotherapy trials for prostate cancer is a failure. Ipilimumab, an anti-CTLA-4 antibody reported improved PFS with normalization of bone scan, disappearance of bone pain with consistent zero prostate-specific antigen (PSA) slope.
- Programmed cell death protein 1 (PD1) inhibitors also demonstrated clear efficacy in the treatment of CRPC.
- Microsatellite instability (MSI) is a very important biomarker for prostate cancer to know about patients who might benefit with immunotherapy.
- Inactivation of CDK12 was found in 7% prostate cancer patients, it might be a good way to identify patients who benefited from immunotherapy.
- Enhanced rPFS benefit was observed in patients with homologous recombination DNA damage repair deficiency (HRD+) or DNA damage repair (DDR+) tumors.
- Tumor mutation burden (TMB) was suggested as a good way to identify prostate cancer patients who benefitted from CTLA4 and PD1 targeting. High TMB (above the median) was associated with prolonged rPFS vs. low TMB (below the median) (P < 0.0001).
- Transmembrane protein prostate specific membrane antigen (PSMA) is best available target used for identification of prostate cancer by imaging.
- 177LU-PSMA-617 used to target prostate cancer cells showed dramatic efficacy in patients not responding to next generation hormonal therapy and Taxane.
- Phase III trial (Vision) is in progress for the approval of PSMA-Lutetium and also to compare the OS of patients receiving 177Lu-PSMA-617 with SOC versus patients treated with SOC alone.
- Conclusions: Early treatment clearly seems to be better (M1 CSPC, M0 CRPC) and sequential treatment is still routinely used in 2020 for CRPC. Combinations are experimental and Taxanes are still active after Abiraterone/Enzalutamide.
Question and Answer Session (1st Webinar- 12th May 2020)
Q1: Andrey Soares- How long does ADT can be used as a single treatment agent for treating metastatic prostate cancer before switching to (adding) another therapy (Abiraterone, Docetaxel and may be Enzalutamide)?
Q2: In CRPC, whether we should continue ADT?
Q3: Dr. Andrey Soares – Any patient that (Dr. Fizazi) you would prescribe a new hormonal agent without treatment with ADT?
Ans: Dr. Fizazi responded by referring to the pivotal trials, in all the trials (Abiraterone, Enzalutamide, Docetaxel) in Castration sensitive setting, a 3‑month window period was allowed before using a second agent
For the second question, Dr. Fizazi responded: In CRPC, there is no phase III evidence, we do it continuously and personally I think we should do it.
Can new hormonal agents be used alone? Dr. Fizazi responded that the SOC for patients is ADT, in combination with AR antagonists. It is a doable approach based on previous data with Enzalutamide and might be less toxic. It is encouraging that the American Society of Clinical Oncology (ASCO) has accepted the LACOG 0415 study evaluating this hypothesis and I am keen to see it. However, probably we would need large trial before we really change the practice including cost effectiveness data.
Q3: Dr. Andrey Soares – What are the criteria to change a therapy when using a new hormone agent?
Ans: Dr. Fizazi assumed it to be the case of mCRPC suggesting classical criteria that were used in previous trials (to be followed) which include using at least two out of three parameters of interest not going the way as expected as deciding factors. These parameters include; increased PSA, clinical deterioration, and worsening shown by imaging. This is also recommended by consensus conferences.
Dr. Fizazi also mentioned that he disagrees this to be the course of action at least in some scenarios, because this was used in phase III trial settings, where patients are kept on experimental drug to allow
sufficient exposure to the drug. Medically speaking, there are exceptions; for example, if (I) see a man with a rapidly rising PSA and doubling time of PSA is very rapid and even if he has no clinical deterioration and no imaging deterioration, (I) would start discussion with patient regarding whether we should switch him to another drug. Not necessarily (today) immediately, but at least (to) prepare him and start seeing him more frequently because (I) know this patient can deteriorate rapidly, and to explain the further treatment strategy. And ethically (I think) continuing the drug and waiting for the symptoms to appear is not necessarily good thing to do. Dr Fizazi said that rather he would treat the patient with intent to prevent symptoms from occurring which he stated as his personal opinion. But talking about consensus recommendations, it has to be either clinical deterioration or imaging deterioration, not only PSA deterioration.
Q4: Dr. Andrey Soares – If doubling time of PSA is a good marker for the bad disease and asked in patients with metastatic CRPC, the doubling might be 8 months, 10 months. How to handle situation in mCRPC patients?
Ans: Dr. Fizazi said that there is no true cut off for this. He referred M0 CRPC where 10 month or less than 10 months PSA doubling time was considered. Patients kept in various class of PSA doubling time viz 0-3 month, 3-6 months, and 6-10 months. In all the cases, patients benefitted the same from the intervention given. Hence, there is no real cut off as it is more like a prognostic factor and not a predictive factor. It is very likely to be the same for metastatic CRPC where there is no cut off, generally the more PSA is rising, the disease is worse.
Q5: Dr. Andrey Soares – Mentioning that Latin America has a heterogenous population, Dr. Soares asked what kind of data is available for the treatment in black and white population and whether it is effective in one population set.
Ans: Dr. Fizazi responded by referring a trial involving black patients with Docetaxel 2 years ago by Susan Halabi, 2019 with an intent to show that black patients seem to benefit at least as good as others from chemotherapy. It was interesting since people believed that outcome would be worse among black population. The reason attributed is to their higher socio-economic status, as those entered in trial were rich and not the poor which is the case usually. He concluded by saying that data is still scarce and there is one race which is the human race that exist. Previous to this was Neanderthals which are gone years ago. As far as ethnicity is concerned in the context of this topic, black people benefitted equally with chemotherapy, but for hormonal therapy they are not sure since this is not
what they actually studied. The data that we have does not necessarily support the differences between the ethnicities but there is data supporting AR targeting might work better for patients from Asia. The reason why black men are at higher risk of developing prostate cancer is because of binding protein and hormones in the blood because of variations from ethnicities, but we are not fully sure.
Extending to the response from Dr. Fizazi, Dr. Soares mentioned that there is no difference in results in either black or white population (50 each) with Abiraterone based on previous data from ASCO, (but the they recruited more black patients since the dropout rate was more among black as only 10% lasted in the trials. PSA response or PSA free survival was a little bit better for black population but the toxicity profile was different, may be because of some enzyme involved.
Dr. Fizazi further commented that Brazil can actually afford to recruit more black population as they have big black population.
Q6: Dr. Andre Soras asked if Dr. Fizazi would prefer considering Docetaxel over the new hormonal therapy seeing /neuroendocrine features?
Ans: Dr. Fizazi responded by saying that it is not really known since the men with neuroendocrine differentiation were excluded in trials with Abiraterone or Enzalutamide so, we don’t know efficacy. From personal experience (Dr. Fizazi) it is worse. Neuroendocrine differentiation doesn’t mean it is a neuroendocrine tumor it still remains an adenocarcinoma mainly. Biological / Genomic data from west coast is provocative and AR remains present.
Q7. We know from previous data new hormonal therapy followed by another one is not a good strategy, however in COVID-19 times, do you think you change your sequencing strategy of (irrespective of sensitive/resistant setting) to postpone / avoid chemotherapy?
Probably reasonable doing, when cancer is not progressing rapidly especially in men who benefited longer with Abiraterone as first hormonal therapy, I would certainly consider switching him to Enzalutamide in COVID times.
If patient has not benefitted long with Abiraterone and has rapid progression, then I think Docetaxel should be considered with G_CSF support, keeping in mind risk and benefit analysis.
Question and Answer Session (2nd Webinar- 19th May 2020)
Q1: Dr. Malwinder – Should the dose of Abiraterone be reduced to 1 tablet due to cost constraint. What diet would be recommended for patient on a single tablet of Abiraterone? Also, what are the evidences behind it?
Ans: Dr. Fizazi responded by mentioning that Abiraterone in phase I trial was tested with and without food and it was noted that amount of drug that goes into the blood or circulation (Absorption) is not the same depending on the amount of food taken. To achieve a stable pharmacokinetic (PK) of Abiraterone, it was originally recommended to use the drug without the food as it seems more stable without food. But higher dose was required to achieve higher level of PK. This is how the Abiraterone was subsequently used for phase III development. All the phase III data discussed was with 1 gm of steroids and without food. He also discussed about a randomized phase II trial from Canada which reported that if Abiraterone is used with food, dose can significantly be lowered from 1 gm to 250 mg along with corticosteroids which would result in achieving very similar PK and more importantly very similar anti-cancer efficacy. However, we don’t know whether this is also true in terms of OS but at least response and progression free survival seem to be similar to that of 1gm dose without food. Hence, for patients who cannot afford dose of 1 gm/day of the drug without food, it is very reasonable to prescribe 250 mg of the drug with food if they can afford it and if they can afford for longer duration.
Dr. Malwinder further added by asking does the above recommendation has to be with food or more specifically with low fat food?
Dr. Fizazi responded by saying that main recommendation is without the food, generally 2 hours after the patient had meal or at least 1 hour before taking next meal. If using 250 mg with food, it was recommended to have the drug with heavy breakfast which includes some fat.
Q2: Dr. Malwinder – In the COVID era, when we are using Abiraterone, we get the blood test done every month or so, is it possible to extend blood testing or monitoring to 3 months? (Monitoring patient on Abiraterone therapy)
Ans: Dr. Fizazi – It depends how difficult it is since we have to count what we gain versus what we lose. If we miss blood testing every 2 weeks or 4 weeks, we might miss some hypokalemia and rarely some liver test increases which could be an issue. Basically, if a patient has to wait for long to get the
blood test done with lots of patients around (him before blood collection), probably it is risky to do that every 2-4 weeks. However, if things are well organized and patient has an appointment done at a fixed time and he/she does not get in touch with anyone. In this case, it does not seem like a big risk for the patient to get infected with COVID-19. Hence, it more or less depends on what type of infrastructure is available (locally / at your center).
Q3: Dr. Malwinder- What is the logic behind different doses of steroid administration such as CSPC it is lower and in CRPC it is higher and whether can we switch prednisone to dexamethasone?
Ans: Dr. Fizazi – Regarding the use of prednisone with Abiraterone 10 mg, the phase I trials indicated that steroid (co-administration) was needed. It was actually hard to decide which steroid to be used. COUGAR biotech, the first company that developed Abiraterone decided to conduct phase III CRPC studies with Prednisone 10 mg. Post these studies the company felt that 10 mg of Prednisone could be reduced to 5 mg in LATTITUDE phase III trial. Actually, what was observed in the Latitude trial as a result was slightly more hypokalemia and hypertension than what was observed in CRPC studies. Hence, we can decide either 5 of 10 mg dose weighing the pros and cons. But the most important thing is that whatever the dose we are choosing, it is to make sure that we are monitoring the patient. For example, if a patient is developing hypokalemia or hypertension on 5 mg, it might be an indicator that the dose of prednisone is not high enough to prevent the feedback on ACTH and hyper-mineralo corticosteroidism. So, we might want to increase dose from 5 mg to 10 mg and keep monitoring for hypokalemia and hypertension. In case, patients gaining weight we might reduce from 10 mg to 5 mg and this is actually my (Dr. Fizazi) practice.
Regarding what choice of steroids to be given with Abiraterone, we have data that indicate that Dexamethasone and even a Hydroxycortisone might be a better partner. Actually when patients progressing with Abiraterone and Prednisone are switched to Dexamethasone and continue with Abiraterone, (which means replacing Prednisone with Dexamethasone), we might notice that ~30% of the men will benefit, experiencing drop in PSA and also clinical improvements sometimes just by switching the corticosteroids. These men might actually have AR mutations that make AR being stimulated by prednisone, hence switch to Dexamethasone improve things. But using Dexamethasone upfront is little bit difficult because all phase III trials were conducted with Prednisone. So, we don’t know if Dexamethasone upfront would result same outcomes as that of Prednisone
Q4: Dr. Malwinder to both Dr. Ong and Dr. Fizazi – What is the adverse event related to drop off for Abiraterone and what about dose titration of patients with toxicities?
Ans: Dr. Ong – Responded by saying as mentioned by Dr. Fizazi, we will begin with dose adjustments. Dr. Fizazi said that in his experience only minority of men (need to) discontinued with Abiraterone due to the toxicities, if (we are) monitoring them correctly, and considering dose reductions or dose increase in steroids or supplementation in potassium or use of anti-hypertension drugs, then majority of the patients can continue with Abiraterone.
Q5: Dr. Malwinder – Do we have any evidence or data to support the use of Docetaxel in M0 castrate resistant prostate cancer besides hormonal therapies like in SPARTAN and ARAMIS trials?
Ans: Dr. Fizazi – For M0 castration disease, the answer is no, as we have zero randomized data and actually minimal non-randomized data for Docetaxel for M0CRPC. We do have some data in men with high risk of localized disease. So, for patients who are starting with treatment for localized disease, for example T3 disease, high Gleason score, high PSA value to be given radiation or androgen deprivation therapy, we have data that we reported last year at the European Society for Medical Oncology, for example, STAMPEDE data. Most of the data point in the same direction relapse free survival using PSA is a way to detect relapse is actually improved by the early use of the Docetaxel. But regarding stronger endpoints, such as metastasis free survival or OS, we don’t have evidence at the moment. Colleagues from England (UK) are using Docetaxel routinely in high risk localized disease to give radiation with ADT but that is not being practiced (outside UK) in France.
Q6: Dr. Malwinder – One of the participants has many metastatic prostate cancer patients and their PSA rise slowly but there is no progression on imaging, testosterone is within castration level and patient has no symptoms. What to do next? Do we start use of Abiraterone or follow up closely or look for the doubling of the PSA or velocity of PFS increase?
Ans: Dr. Fizazi- So this is a metastatic disease patient with CRPC with slow progression – There are two options, although it is hard to comment which is best. If the disease seems to be indolent and patient is asymptomatic and PSA is rising slowly, then either he should go to next generation hormonal therapy such as Abiraterone and we have data supporting this COU-AA-302 for e.g. The second is you just wait or use old generation (hormonal agent) manipulation which is cheaper etc. (just carry on with castration) but if you do that, it is required that you monitor patients very seriously
and if your patient is progressing faster such rapid rise in PSA or imaging deterioration or clinical deterioration, make sure to treat patient on time. Key thing here is monitoring especially if you are not using immediate intervention.
Q7: Dr. Malwinder– For certain countries Docetaxel is covered by the local health insurance, however, Abiraterone is not covered by the local health insurance. Looking at the toxicity profile and the benefit, is it logical to just prescribe patients with Docetaxel upfront?
Ans: Dr. Fizazi – It needs to be decided on individual basis because in men with de-novo metastatic disease. I think it is fair to say that Abiraterone is better in terms of safety, quality of life, probably in terms of symptom control (pain control), in terms of progression free survival. Abiraterone has achieved better control of the disease in the longer run as compared with Docetaxel and even OS. We observed 35% reduction in the risk of death with Abiraterone and other AR targeting agents and less than 20% with chemotherapy. In conclusion, Abiraterone is better and the only thing favoring Docetaxel is the cost. So, discussion is required on individual basis with your patient depending on the system (how much is coverage, is patient willing to pay for his health). But (while) providing him medical data, it would be unfair to say that Abiraterone and Docetaxel are same, which is not true. Abiraterone is better on various parameters as we have seen (in lecture) except cost, and then you have to make a decision or your patient has to.
Q8: Dr. Malwinder – In the treatment with PSMA, if a patient has a new uptake lesion PSMA. What is the proper treatment? Do we continue with the PSMA or do we consider a new treatment or combine a new treatment with PSMA?
Ans: Dr. Fizazi – We actually don’t really know the answer at the moment. In a phase II trial that was just reported, PSMA treatment was used as a single agent with castration (obviously) but not with the drugs like Abiraterone, chemotherapy, Enzalutamide etc. In VISION trial, the best SOC was used alone or in combination with Lu-PSMA. So, if we are using Abiraterone or Enzalutamide as the best SOC in the patient or control arm, it was also given with Lu-PSMA to the patient in the experimental arm, so VISION trial will give us data about combo. A randomized Australian data will be reported in American Society of Clinical Oncology (ASCO), which will be single agent with Lu-PSMA. These 2 trials will complement and we will learn from that.
Q9: Dr. Malwinder - Is there any role for local therapy for M0 castrate resistant cancer in clinically asymptomatic patients?
Ans: Dr. Fizazi – It is difficult to answer but answer would be regarding the treatment of the primary cancer. Based on the STAMPEDE data, we now have at least an evidence that indeed radiation therapy is associated with improvement of OS when using prostate cancer primary directed radiation in men with oligo metastatic disease. Now whether targeting metastasis is also associated with improved outcomes is something that we do not know. We have only retrospective analysis and one small randomized trial with only 60 patients. So, it will be too early to say and phase III trials are currently underway to address this question.
Q10: Dr. Malwinder – What is the role of PARP inhibitor in castration sensitive metastatic prostate cancer who has BRCA-2 mutations. Can we use it before Abiraterone or Enzalutamide?
Ans: Dr. Fizazi – We do not have data at the moment. The only data that we have from phase II and now from phase III PROFOUND trials was for patients who have failed with Abiraterone or enzalutamide and most often who had failed Docetaxel. There are trials starting or being planned in Abiraterone or Enzalutamide naïve setting but we do not know as of now.
Q11: Dr. Malwinder – Is there any recommendation in case of diabetic with castrated prostate in terms of treating with steroids. Do you reduce the use of steroids in them or anyone with heart problem?
Ans: Dr. Fizazi – This is the situation where he will use 5 mg of prednisone and look at the diabetes closely. In patients with very unbalanced diabetes where it is impossible to equilibrate, if you have a choice you would use enzalutamide and not Abiraterone because of steroid co-medication. Honestly, it is very infrequent, but if it happens, it could be an exception, Enzalutamide would be used. However, in case of normal diabetes not very hard to equilibrate, (he/I) considers using Abiraterone with 5 mg of prednisone and monitor the diabetes.
Q12: Dr. Malwinder – What is the PSA reading that would be sensitive on uptake of PSMA positron emission tomography (PET)?
Ans: Dr. Fizazi – Approximately 90% of the patients with advance stage prostate cancer we will have a positive PET PSMA. For example if you are doing a PET PSMA in man with normal bone scan and a normal Computed Tomography (CT) scan and CRPC, patients we enrolled in SPARTAN, PROSPER ARAMIS for e.g. if you do a PET PSMA will find, wherever the disease is located, the
PET PSMA will locate the disease in 96% or almost 100% of patients which is a very good imaging. It has some false negatives and false positives, but it will help.
Dr. Malwinder extended by asking if there is any PSA level cut off? For example, person with PSA 10 will he have an uptake?
Dr. Fizazi responded by saying that it actually depends mostly on PSA pace, with most rapid PSA doubling time, the highest the incidence of positive PET PSMA occurs.