THE "NEW" PROSTATE CANCER INFOLINK

A poster presented at the ESMO meeting in Munich has just reported data from an unplanned, preliminary analysis of data from the first 85 patients (out of a scheduled total of 150 patients) enrolled in the TRITON 2 trial of the PARP inhibitor rucaparib (Rubraca) in treatment of men with metastatic, castration-resistant prostate cancer (mCRPC) and one or more of 15 different deleterious germline or somatic alterations in prespecified homologous recombination repair (HRR) genes.

Detailed information about this presentation (given by Dr. Wassim Abida, of the Memorial Sloan-Kettering Cancer Center, and principal investigator for the TRITON2 study) is available in a media release from the developer of rucaparib (Clovis Oncology) and also in a commentary on the UroToday web site. The complete poster is already accessible on the Clovis Oncology web site (see here), as is a second and related poster that deals with the genomic profiling of circulating tumor DNA and tumor tissue from patients enrolled in this trial (see here).

Some context is perhaps necessary to understand this presentation and the data therein.

1. It is not entirely clear why Clovis Oncology decided to conduct this somewhat unusual, unplanned, preliminary analysis, but one assumes that it has to have been approved by the independent data monitoring committee for the TRITON 2 trial based on the outcomes being observed from early enrollees in the trial.
2. Apparently, the data presented at ESMO are the data that were used to support a breakthrough therapy designation for rucaparib in the treatment of men with mCRPC and germline BRCA1/2 gene mutations issued by the FDA on October 2 this year (see here).
3. There is no sign that Clovis Oncology had ever announced that it had made such an application to the FDA for a breakthrough therapy designation prior to the receipt of the designation on October 2.

Note that a “breakthrough therapy” designation does not mean or imply that a drug is approved for the treatment of a disease. It simply indicates that the product shows particular promise in treatment of a specific set of well-defined patients and that data presented to the FDA by the drug’s developer will be prioritized by the FDA when it is complete and submitted for formal FDA review.

So, with that context, here are the basic data that were presented by Abida and his colleagues in their poster at the ESMO 2018 Congress in Munich over the weekend.

• The TRITON 2 trial is an open-label Phase II trial of treatment with rucaparib for men who
  • Have mCRPC
  • Have progressive disease after prior treatment with at least one form of androgen deprtivation therapy (ADT) and taxane-based chemotherapy
  • Had been screened for the presence a deleterious germline or somatic alteration in BRCA1, BRCA2, or one of 13 other pre-specified homologous recombination (HR) genes.
• Patients in the trials are divided into three cohorts:
  • Men with an alteration in any one of the BRCA1, BRCA2, or ATM genes, with tumors that can be measured with visceral and/or nodal disease (Group A)
  • Men with an alteration in any one of the BRCA1, BRCA2, or ATM genes, with tumors that can not be measured with visceral and/or nodal disease (Group B)
  • Men with an alteration in one of 12 other HR genes associated with sensitivity to PARP inhibition, with or without measurable disease (Group C)

The cut-off date for the collection of the data presented at the ESMO Meeting was June 29, 2018, and here are the basic data reported:

• 85 patients had been treated with rucaparib as of that date.
• The average (median) treatment duration was
  • 3.7 months  (range, 0.5 to 12.9 months) for all 85 patients
  • 4.4 months (range, 0.5 to 12.0 months) for patients with a BRCA1/2 mutation
• The average (median) follow-up for all 85 patients was 5.7 months (range, 2.6 to 16.4 months).
• 46/85 patients (54.1%) were evaluable for RECIST/PCWG3 response, including 25 patients with a BRCA1/2 alteration.
• Based on investigator-assessed RECIST/PCWG3, the confirmed overall response rate (ORR) in patients with a BRCA1/2 alteration was 44.0 percent (i.e., 11/25 patients).
• Among the 45 evaluable patients with a BRCA1/2 alteration, 51.1 percent (23/45) had a confirmed PSA response.
• It is unclear (for technical reasons) whether any patients with an ATM mutation (but no BRCA1/2 mutation) responded to therapy.
• Patients with a CDK12 mutation did not respond to therapy (ORR = 0 percent or 0/8), and the investigators have stopped patients with this mutation.
• The most common treatment-emergent adverse events (TEAEs) of any grade in all patients, regardless of causality, included:
  • Asthenia/fatigue (44.7 percent, or 38/85)
  • Nausea (42.4 percent, or 36/85)
  • Anemia/decreased hemoglobin (22.4 percent, or 19/85)
  • Constipation (28.2 percent, or 24/85)
• Just over half of the 85 patients (52.9 percent) had at least one treatment interruption as a consequence of TEAEs, but most were subsequently able to resume treatment.
• 5/85 patients (5.9 percent) discontinued therapy due to a non-progression TEAE.
• 1/85 patients (1.12 percent) died due to disease progression.

Now clearly the FDA believes that this trial and the currently available data do show that the use of rucaparib can be effective in the treatment of at least half of the patients who have a BRCA1/2 mutation and who have mCRPC (i.e., many of the men in Groups A and B) who have been treated to dated.

On the other hand, (a) the average duration of treatment to date has been brief and treatment comes with significant side effects; (b) the available data give us no real indication ad to the duration of patient response post-treatment (let alone any impact on overall survival).

It is therefore difficult for us to know, as yet, just what the risk/benefit ratio for treatment with rucaparib may be for men with mCRPC who also have a BRCA1/2 mutation, let alone any 12 of the other 13 mutations, that allowed for enrollment in this trial. While the overall response rate is certainly interesting, the real questions that remain unanswered are these:

• Can PARP inhibitors significantly extend the survival of men with specific types of alteration to HRR genes like BRCA1/2 and others?
• Do PARP inhibitors have broader utility in the treatment of earlier or later stages of prostate cancer or is utility limited to men with specific types of alteration to HRR genes?
• When is the most appropriate time to implement such therapy to maximize benefit and minimize risk?
• When should one be testing potential candidates for the presence of specific mutations to HRR genes and how does one determine who needs such genetic/genomic testing?

It seems that we have a ways to go before all these questions can be well answered.

Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: inhibitor, PARP, Rubraca, rucaparib, trial, TRITON 2 |